Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors

ABSTRACT

The present application provides imidazolyl pyrimidinylamine inhibitors of cyclin-dependent kinase 2 (CDK2), as well as pharmaceutical compositions thereof, and methods of treating cancer using the same.

This application claims the benefit of priority of U.S. Prov. Appl. No.62/886,735, filed Aug. 14, 2019, which is incorporated herein byreference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been filedelectronically in ASCII format and is hereby incorporated by referencein its entirety. Said ASCII copy, created on Aug. 12, 2020, is named20443-0628001SEQ.txt and is 15.5 kilobytes in size.

TECHNICAL FIELD

This application is directed to imidazolyl pyrimidinylamine compoundswhich inhibit cyclin-dependent kinase 2 (CDK2) and are useful fortreating cancer.

BACKGROUND

Cyclin-dependent kinases (CDKs) are a family of serine/threoninekinases. Heterodimerized with regulatory subunits known as cyclins, CDKsbecome fully activated and regulate key cellular processes includingcell cycle progression and cell division (Morgan, D. O., Annu Rev CellDev Biol, 1997. 13: 261-91). Uncontrolled proliferation is a hallmark ofcancer cells. The deregulation of the CDK activity is associated withabnormal regulation of cell-cycle, and is detected in virtually allforms of human cancers (Sherr, C. J., Science, 1996. 274(5293): 1672-7).

CDK2 is of particular interest because deregulation of CDK2 activityoccurs frequently in a variety of human cancers. CDK2 plays a crucialrole in promoting G1/S transition and S phase progression. In complexwith cyclin E (CCNE), CDK2 phosphorylates retinoblastoma pocket proteinfamily members (p107, p130, pRb), leading to de-repression of E2Ftranscription factors, expression of G1/S transition related genes andtransition from G1 to S phase (Henley, S. A. and F. A. Dick, Cell Div,2012, 7(1): p. 10). This in turn enables activation of CDK2/cyclin A,which phosphorylates endogenous substrates that permit DNA synthesis,replication and centrosome duplication (Ekholm, S. V. and S. I. Reed,Curr Opin Cell Biol, 2000. 12(6): 676-84). It has been reported that theCDK2 pathway influences tumorigenesis mainly through amplificationand/or overexpression of CCNE1 and mutations that inactivate CDK2endogenous inhibitors (e.g., p27), respectively (Xu, X., et al.,Biochemistry, 1999. 38(27): 8713-22).

CCNE1 copy-number gain and overexpression have been identified inovarian, gastric, endometrial, breast and other cancers and beenassociated with poor outcomes in these tumors (Keyomarsi, K., et al., NEngl J Med, 2002. 347(20): 1566-75; Nakayama, N., et al., Cancer, 2010.116(11): 2621-34; Au-Yeung, G., et al., Clin Cancer Res, 2017. 23(7):1862-1874; Rosen, D. G., et al., Cancer, 2006. 106(9): 1925-32).Amplification and/or overexpression of CCNE1 also reportedly contributeto trastuzumab resistance in HER2+ breast cancer and resistance toCDK4/6 inhibitors in estrogen receptor-positive breast cancer(Scaltriti, M., et al., Proc Natl Acad Sci USA, 2011. 108(9): 3761-6;Herrera-Abreu, M. T., et al., Cancer Res, 2016. 76(8): 2301-13). Variousapproaches targeting CDK2 have been shown to induce cell cycle arrestand tumor growth inhibition (Chen, Y N., et al., Proc Natl Acad Sci USA,1999. 96(8): 4325-9; Mendoza, N., et al., Cancer Res, 2003. 63(5):1020-4). Inhibition of CDK2 also reportedly restores sensitivity totrastuzumab treatment in resistant HER2+ breast tumors in a preclinicalmodel (Scaltriti, supra).

These data provide a rationale for considering CDK2 as a potentialtarget for new drug development in cancer associated with deregulatedCDK2 activity. In the last decade there has been increasing interest inthe development of CDK selective inhibitors. Despite significantefforts, there are no approved agents targeting CDK2 to date (Cicenas,J., et al., Cancers (Basel), 2014. 6(4): p. 2224-42). Therefore itremains a need to discover CDK inhibitors having novel activityprofiles, in particular those targeting CDK2. This application isdirected to this need and others.

SUMMARY

The present invention relates to, inter alia, compounds of Formula (I):

or pharmaceutically acceptable salts thereof, wherein constituentmembers are defined herein.

The present invention further provides pharmaceutical compositionscomprising a compound described herein, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides methods of inhibiting CDK2,comprising contacting the CDK2 with a compound described herein, or apharmaceutically acceptable salt thereof.

The present invention further provides methods of inhibiting CDK2 in apatient, comprising administering to the patient a compound describedherein, or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating a disease ordisorder associated with CDK2 in a patient, comprising administering tothe patient a therapeutically effective amount of the compound describedherein, or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a humansubject having a disease or disorder associated with cyclin-dependentkinase 2 (CDK2), comprising administering to the human subject acompound described herein, or a pharmaceutically acceptable saltthereof, wherein the human subject has been previously determined to:(i) (a) have a nucleotide sequence encoding a p16 protein comprising theamino acid sequence of SEQ ID NO:1; and/or (b) have a cyclin dependentkinase inhibitor 2A (CDKN2A) gene lacking one or more inactivatingnucleic acid substitutions and/or deletions; (ii) (a) have anamplification of the cyclin E1 (CCNE1) gene; and/or (b) have anexpression level of CCNE1 in a biological sample obtained from the humansubject that is higher than a control expression level of CCNE1.

The present invention additionally provides methods of treating a humansubject having a disease or disorder associated with cyclin-dependentkinase 2 (CDK2), comprising: (i) identifying, in a biological sampleobtained from the human subject: (a) a nucleotide sequence encoding ap16 protein comprising the amino acid sequence of SEQ ID NO:1; and/or(b) a cyclin dependent kinase inhibitor 2A (CDKN2A) gene lacking one ormore inactivating nucleic acid substitutions; (ii) identifying, in abiological sample obtained from the human subject: (a) an amplificationof the cyclin E1 (CCNE1) gene; and/or (b) an expression level of CCNE1that is higher than a control expression level of CCNE1; and (iii)administering a compound described herein, or a pharmaceuticallyacceptable salt thereof, to the human subject.

The present invention also provides methods of evaluating the responseof a human subject having a disease or disorder associated withcyclin-dependent kinase 2 (CDK2) to a compound described herein, or apharmaceutically acceptable salt thereof, comprising: (a) administeringthe compound or the salt, to the human subject, wherein the humansubject has been previously determined to have an amplification of thecyclin E1 (CCNE1) gene and/or an expression level of CCNE1 that ishigher than a control expression level of CCNE1; (b) measuring, in abiological sample of obtained from the subject subsequent to theadministering of step (a), the level of retinoblastoma (Rb) proteinphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3, wherein a reduced level of Rb phosphorylation at theserine corresponding to amino acid position 780 of SEQ ID NO:3, ascompared to a control level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3, is indicativethat the human subject responds to the compound or the salt.

The present invention further provides a compound described herein, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound describedherein, or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament for use in any of the methods describedherein.

DESCRIPTION OF DRAWINGS

FIGS. 1A-1B: Characterization of ovarian and endometrial cell lines.FIG. 1A: Cell lines used for study included four cell lines with CCNE1amplification and three cell lines with no CCNE1 amplification. CCNE1amplification copy numbers are indicated. FIG. 1B: The expression ofCCNE1 was determined by Western blot in indicated cell lines. This blotshow cell lines with CCNE1 gain of function by copy number (CN>2)expressed higher levels of CCNE1 protein compared with cell lines withcopy neutral or loss of function of the gene (CN≤2). GAPDH was detectedas a loading control. Non-Amp, non-amplification; Amp, amplification.

FIGS. 2A-2B: siRNA mediated CDK2 knockdown inhibits proliferation inCCNE1 amplified cell lines. FIG. 2A: CCNE1 amplified Fu-ov1 (upper) andKLE (lower) cells were harvested and subjected to cell cycle analysis 72hours after transfection with either scrambled siRNAs (“Ctl”) or CDK2siRNAs. The cell cycle phase distribution was evaluated by FACS. Shownare representative images of three separate experiments. FIG. 2B: CDK2knockdown was confirmed by Western blot analysis after transfection withCDK2 siRNA. GAPDH was used as a loading control.

FIGS. 3A-3B: CDK2 knockdown does not inhibit proliferation in CCNE1Non-Amp lines. FIG. 3A: CCNE1 non-amplified COV504 and Igrov1 cells wereharvested and subjected to cell cycle analysis 72 hours aftertransfection with Ctl siRNAs and CDK2 siRNAs. The cell cycle phasedistribution was evaluated by FACS. Shown are representative images ofthree separate experiments. FIG. 3B: CDK2 knockdown was confirmed byWestern blot analysis after transfection with CDK2 siRNA. GAPDH was usedas a loading control.

FIG. 4: CDK2 knockdown by siRNA inhibits proliferation in CCNE1amplified, but not in CCNE1 non-amplified, human cancer cell lines.Percentage of cells at the S phase 3 days after transfection of CDK2siRNAs, relative to Ctl siRNA. The cell cycle phase distribution wasevaluated by FACS. Means represent three independent experiments in fourCCNE1 Amp cell lines and three Non-Amp lines.

FIG. 5: Palbociclib treatment induces dose-dependent inhibition ofproliferation in CCNE1 non-amplified, but not in amplified cell lines.Cell cycle analysis of CCNE1 non-amplified cell line COV504 (upper) andCCNE1 amplified OVCAR3 cells (lower) after Palbociclib treatment for 16hours. The cell cycle phase distribution was evaluated by FACS.

FIG. 6: Palbociclib treatment selectively inhibits proliferation inCCNE1 non-amplified cancer cell lines. Percentage of cells at the Sphase after 16 hours of Palbociclib with the indicated doses, relativeto DMSO.

FIGS. 7A-7B: CDK2 knockdown by siRNAs blocks RB phosphorylation at 5780in CCNE1 amplified, but not in non-amplified ovarian cells. FIG. 7A:Four CCNE1 Amp cell lines, COV318, Fu-OV1, OVCAR3 and KLE cells, weretransfected with CDK2 siRNAs for 72 hours. FIG. 7B: Three CCNE1 Non-Ampcell lines, COV504, OV56 and Igrov1, were transfected with CDK2 siRNAsfor 72 hours. The total proteins were extracted from CDK2 siRNA or CtlsiRNA transfected cells and subjected to western blotting. GAPDH wasused as a loading control.

FIGS. 8A-8B: Palbociclib blocks RB phosphorylation at 5780 in CCNE1non-amplified, but not in amplified ovarian cells. FIG. 8A: CCNE1 AmpOVCAR3 and COV318 cells were treated at various concentrations ofPalbociclib as indicated for 1 hour or 15 h. FIG. 8B: CCNE1 Non-AmpCOV504 and OV56 were treated at various concentrations of Palbociclib asindicated for 1 hour or 15 h. The total proteins were extracted fromthese Palbociclib or DMSO (controls) treated cells and subjected towestern blotting. p-RB, phosphorylated retinoblastoma protein. GAPDH wasused as a loading control.

FIGS. 9A-9B: CDK2 degradation by dTAG decreases RB phosphorylation at5780. FIG. 9A: Chemical structure of dTAG. FIG. 9B: CDK2-FKBP12(F36V)degradation by CDK2-dTAG treatment for 14 hours inhibited RBphosphorylation at 5780 in CDK2 knockout OVCAR3 (right, Cas9+,CDK2-FKBP12(F36V)-HA+, CDK2-gRNA) cells, but not in OVCAR3 cells withendogenous CDK2 (left, Cas9+, CDK2-FKBP12(F36V)-HA+, Ctl-gRNA).

FIGS. 10A-10B: p-RB S780 HTRF cellular Assay for identification of CDK2inhibitors. FIG. 10A: IC₅₀ in CDK2 biochemical kinase activity assay.FIG. 10B: Concentration response analysis of reference compounds testedin the p-RB S780 HTRF cellular assay. HTRF, homogeneous time-resolvedfluorescence. IC₅₀ from HTRF cellular Assay correlates with IC₅₀ in CDK2enzymatic assay.

FIG. 11: Bioinformatics analysis of CCLE dataset reveals the sensitivityto CDK2 inhibition in CCNE1 amplified cells relies on functional p16.FIG. 11 shows the status of p16 in CDK2 sensitive verse insensitive celllines. CCLE: Broad Institute Cancer Cell Line Encyclopedia (seeBarretina, below).

FIGS. 12A-12B: CCNE1 amplified cells with dysfunctional p16 do notrespond to CDK2 inhibition. FIG. 12A: Western blot analysis of p16 inthree gastric cell lines with CCNE1 Amp. FIG. 12B: Percentage of cellsat the S phase 3 days after transfection of CDK2 siRNAs, relative to CtlsiRNA. The cell cycle phase distribution was evaluated by FACS.

FIG. 13: p16 knockdown by siRNA abolishes CDK2 inhibition induced cellcycle suppression in CCNE1 amplified cells. The percentage of S phasecells following p16 knockdown and CDK2 inhibitor treatment, normalizedto cell with Ctl siRNA and DMSO treatment. CCNE1 amplified COV318 cellswere transfected with either Ctl siRNAs or p16 siRNA. 72 hours aftertransfection, cells were treated with 100 nM CDK2 inhibitor Compound A.Cells were harvested and subjected to cell cycle analysis 16 hours aftertreatment.

DETAILED DESCRIPTION

The present application provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, or 4;

Ring moiety A is 4-14 membered heterocycloalkyl, wherein Ring moiety Ais attached to the —NH— group of Formula (I) at a ring member of asaturated or partially saturated ring of said 4-14 memberedheterocycloalkyl;

R¹ is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, OH, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃alkylamino, di(C₁₋₃ alkyl)amino, cyano-C₁₋₄ alkyl, HO—C₁₋₄ alkyl, C₁₋₃alkoxy-C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;

R², R³, and R⁴ are defined as shown in Group (a), Group (b), or Group(c);

-   -   Group (a):    -   R² is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,        amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, cyano-C₁₋₄ alkyl,        HO—C₁₋₄ alkyl, C₁₋₃ alkoxy-C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;    -   R³ is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, OH, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,        amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, cyano-C₁₋₄ alkyl,        HO—C₁₋₄ alkyl, C₁₋₃ alkoxy-C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; and    -   R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10        membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10        membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered        heteroaryl-C₁₋₄ alkyl, C(O)R^(b4), C(O)NR^(c4)R^(d4),        C(O)NR^(c4)(OR^(a4)), C(O)OR^(a4), C(═NR^(e4))R^(b4),        C(═NR^(c4))NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);        wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂-6        alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered        heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10        membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered        heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2,        3, or 4 independently selected R^(4A) substituents;    -   Group (b)    -   R² is selected from H, D, halo, NO₂, CN, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10        membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered        heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄        alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered        heteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), NHOR^(a2), C(O)R^(b2),        C(O)NR^(c2)R^(d2), C(O)NR^(c2)(OR^(a2)), C(OX)R^(a2),        OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),        NR^(c2)NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(OX)R^(a2),        NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),        C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)C(═NR^(e2))R^(b2), NR^(c2)S(O)NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)(═NR^(e2))R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),        S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2),        OS(O)(═NR^(e2))R^(b2), OS(O)₂R^(b2), S(O)(═NR^(e2))R^(b2), SF₅,        P(O)R^(f2)R^(g2), OP(O)(OR^(h2))(OR^(i2)),        P(O)(OR^(h2))(OR^(i2)), and BR^(j2)R^(k2); wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀        cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,        5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10        membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄        alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl are each        optionally substituted by 1, 2, 3, or 4 independently selected        R^(2A) substituents;    -   R³ is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, OH, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,        amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, cyano-C₁₋₄ alkyl,        HO—C₁₋₄ alkyl, C₁₋₃ alkoxy-C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; and    -   R⁴ is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,        C₂₋₄ alkynyl, cyano-C₁₋₄ alkyl, HO—C₁₋₄ alkyl, C₁₋₃ alkoxy-C₁₋₄        alkyl, and C₃₋₄ cycloalkyl;    -   Group (c):    -   R² is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, OH, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,        amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, cyano-C₁₋₄ alkyl,        HO—C₁₋₄ alkyl, C₁₋₃ alkoxy-C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; and    -   R³ and R⁴, together with the atoms to which they are attached,        form a 5-7 membered heterocycloalkyl ring, which is optionally        substituted by 1, 2, 3, or 4 independently selected R^(4A)        substituents;

each R^(a2), R^(e2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

or, any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-10 membered heterocycloalkylgroup, which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents;

each R^(e2) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl;

each R^(f2) and R^(g2) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,6-10 membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;

each R^(h2) and R^(i2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl;

each R^(j2) and R^(k2) is independently selected from OH, C₁₋₆alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j2) and R^(k2) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(2A) is independently selected from D, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)O)R^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(e21)R^(d21), NR^(c21)NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),C(═NR^(e21))R^(b21), C(═NR^(e21))NR^(c21)R^(d21),NR^(c21)C(═NR^(e21))NR^(c21)R^(d21), NR^(c21)C(═NR^(e21))R^(b21),NR^(c21)S(O)NR^(c21)R^(d21), NR^(c21)S(O)R^(b21), NR^(c21)S(O)₂R^(b21),NR^(c21)S(O)═NR^(e21))R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21),S(O)R^(b21), S(O)NR^(c21)R^(d21), S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21),OS(O)(═NR^(e21))R^(b21), OS(O)₂R^(b21), (O)(═NR^(e21))R^(b21), SF₅,P(O)R^(f21)R^(g21), OP(O)(OR^(h21))(OR^(i21)), P(O)(OR^(h21))(OR^(i21)),and BR^(j21)R^(k21), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2B) substituents;

each R^(a21), R^(c21), and R^(d21) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2B) substituents;

or, any R^(c21) and R^(d21) attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, which is optionally substituted with 1, 2, 3, or4 independently selected R^(2B) substituents;

each R^(b21) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents;

each R^(b21) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl;

each R^(f21) and R^(g21) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,6-10 membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;

each R^(h21) and R^(i21) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl;

each R^(j21) and R^(k21) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j21) and R^(k21) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(2B) is independently selected from D, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a22), SR^(a22), NHOR^(a22),C(O)R^(b22), C(O)NR^(c22)R^(d22), C(O)NR^(c22)(OR^(a22)), C(O)OR^(a22),OC(O)R^(b22), OC(O)NR^(c22)R^(d22), NR^(c22)R^(d22),NR^(c22)NR^(c22)R^(d22), NR^(c22)C(O)R^(b22)NR^(c22)C(O)OR^(a22),NR^(c22)C(O)NR^(c22)R^(d22), C(═NR^(e22))R^(b22),C(═NR^(e22))NR^(c22)R^(d22), NR^(c22)C(═NR^(e22))NR^(c22)R^(d22),NR^(c22)C(═NR^(e22))R^(b22), NR^(c22)S(O)NR^(c22)R^(d22),NR^(c22)S(O)R^(b22), NR^(c22)S(O)₂R^(b22),NR^(c22)S(O)(═NR^(e22))R^(b22), NR^(c22)S(O)₂NR^(c22)R^(d22),S(O)R^(b22), S(O)NR^(c22)R^(d22), S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22),OS(O)(═NR^(e22))R^(b22), OS(O)₂R^(b22), S(O)(═NR^(e22))R^(b22), SF₅,P(O)R^(f22)R^(g22), OP(O)(OR^(h22))(OR^(i22)), P(O)(OR^(h22))(OR^(i22)),and BR^(j22)R^(k22), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(2C) substituents;

each R^(a22), R^(c22), and R^(d22) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2C) substituents;

or, any R^(c22) and R^(d22) attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, which is optionally substituted with 1, 2, 3, or4 independently selected R^(2C) substituents;

each R^(b22) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2C) substituents;

each R^(e22) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f22) and R^(g22) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h22) and R^(i22) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j22) and R^(k22) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j22) and R^(k22) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(2C) is independently selected from D, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a23), SR^(a23), NHOR^(a23),C(O)R^(b23), C(O)NR^(c23)R^(d23), C(O)NR^(c23)(OR^(a23)), C(O)OR^(a23),OC(O)R^(b23), OC(O)NR^(c23)R^(d23), NR^(c23)R^(d23),NR^(c23)NR^(c23)R^(d23), NR^(c23)C(O)R^(b23), NR^(c23)C(O)OR^(a23),NR^(c23)C(O)NR^(c23)R^(d23), C(═NR^(e23))R^(b23),C(═NR^(e23))NR^(c23)R^(d23), NR^(c23)C(═NR^(e23))NR^(c23)R^(d23),NR^(c23)C(═NR^(e23))R^(b23), NR^(c23)S(O)NR^(c23)R^(d23),NR^(c23)S(O)R^(b23), NR^(c23)S(O)₂R^(b23),NR^(c23)S(O)(═NR^(e23))R^(b23), NR^(c23)S(O)₂NR^(c23)R^(d23),S(O)R^(b23), S(O)NR^(c23)R^(d23), S(O)₂R^(b23), S(O)₂NR^(c23)R^(d23),OS(O)(═NR^(e23))R^(b23), OS(O)₂R^(b23), S(O)(═NR^(e23))R^(b23), SF₅,P(O)R^(f23)R^(g23), OP(O)(OR^(h23))(OR^(i23)), P(O)(OR^(h23))(OR^(i23)),and BR^(j23)R^(k23), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(G) substituents;

each R^(a23), R^(c23), and R^(d23) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents;

or, any R^(c23) and R^(d23) attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, which is optionally substituted with 1, 2, 3, or4 independently selected R^(G) substituents;

each R^(b23) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(G) substituents;

each R^(e23) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f23) and R^(g23) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h23) and R^(i23) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j23) and R^(k23) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j23) and R^(k23) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4A) substituents;

or, any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-10 membered heterocycloalkylgroup, which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4A) substituents;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂-6 alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4A) substituents;

each R^(e4) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl;

each R^(4A) is independently selected from D, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)NR^(c41)(OR^(a41)), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),C(═NR^(e41))R^(b41), C(═NR^(e41))NR^(c41)R^(d41),NR^(c41)C(═NR^(e41))NR^(c41)R^(d41), NR^(c41)C(═NR^(e41))R^(b41),NR^(c41)S(O)NR^(c41)R^(d41), NR^(c41)S(O)R^(b41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)(═NR^(e41))R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), S(O)₂NR^(c41)R^(d41),OS(O)(═NR^(e41))R^(b41), OS(O)₂R^(b41), S(O)(═NR^(e41))R^(b4), SF₅,P(O)R^(f41)R^(g41), OP(O)(OR^(h41))(OR^(i41)), P(O)(OR^(h41))(OR^(i41))and BR^(j41)R^(k41), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, which is optionally substituted with 1, 2, 3, or4 independently selected R^(4B) substituents;

each R^(b41) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents;

each R^(e41) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl;

each R^(f41) and R^(g41) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,6-10 membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;

each R^(h41) and R^(i41) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl;

each R^(j41) and R^(k41) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j41) and R^(k41) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(4B) is independently selected from D, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a42), SR^(a42), NHOR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)NR^(c42)(OR^(a42)), C(O)OR^(a42),OC(O)R^(a42), OC(O)NR^(c42)R^(c42), NR^(c42)R^(d42),NR^(c42)NR^(c42)R^(d42), NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42),NR^(c42)C(O)NR^(c42)R^(d42), C(═NR^(e42))R^(b42),C(═NR^(e42))NR^(c42)R^(d42), NR^(c42)C(═NR^(e42))NR^(c42)R^(d42),NR^(c42)C(═NR^(e42))R^(b42), NR^(c42)S(O)NR^(c42)R^(d42),NR^(c42)S(O)R^(b42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)(═NR^(e42))R^(b42), NR^(c42)S(O)₂NR^(c42)R^(d42),S(O)R^(b42), S(O)NR^(c42)R^(d42), S(O)₂R^(b42), S(O)₂NR^(c42)R^(d42),OS(O)(═NR^(e42))R^(b42), OS(O)₂R^(c42), S(O)(═NR^(e42))R^(c42), SF₅,P(O)R^(f42)R^(g42), OP(O)(OR^(h42))(OR^(i42)), P(O)(OR^(h42))(OR^(i42)),and BR^(j42)R^(k42), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4C) substituents;

or, any R^(c42) and R^(d42) attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, which is optionally substituted with 1, 2, 3, or4 independently selected R^(4C) substituents;

each R^(b42) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4C) substituents;

each R^(e42) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f42) and R^(g42) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h42) and R^(i42) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j42) and R^(k42) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j42) and R^(k42) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(4C) is independently selected from D, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a43), SR^(a43), NHOR^(a43),C(O)R^(b43), C(O)NR^(c43)R^(d43), C(O)NR^(c43)(OR^(a43)), C(O)OR^(a43),OC(O)R^(b43), OC(O)NR^(c43)R^(d43), NR^(c43)R^(d43),NR^(c43)NR^(c43)R^(d43), NR^(c43)C(O)R^(b43), NR^(c43)C(O)OR^(a43),NR^(c43)C(O)NR^(c43)R^(d43), C(═NR^(e43))R^(b43),C(═NR^(e43))NR^(c43)R^(d43), NR^(c43)C(═NR^(e43))NR^(c43)R^(d43),NR^(c43)C(═NR^(e43))R^(b43), NR^(c43)S(O)NR^(c43)R^(d43),NR^(c43)S(O)R^(b43), NR^(c43)S(O)₂R^(b43),NR^(c43)S(O)(═NR^(e43))R^(b43), NR^(c43)S(O)₂NR^(c43)R^(d43),S(O)R^(b43), S(O)NR^(c43)R^(d43), S(O)₂R^(b43), S(O)₂NR^(c43)R^(d43),OS(O)(═NR^(e43))R^(b43), OS(O)₂R^(b43), S(O)(═NR^(e43))R^(b43), SF₅,P(O)R^(f43)R^(g43), OP(O)(OR^(h43))(OR^(i43)), P(O)(OR^(h43))(OR^(i43)),and BR^(j43)R^(k43), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(G) substituents;

each R^(a43), R^(c43), and R^(d43) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents;

or, any R^(c43) and R^(d43) attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, which is optionally substituted with 1, 2, 3, or4 independently selected R^(G) substituents;

each R^(b43) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(G) substituents;

each R^(e43) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f43) and R^(g43) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h43) and R^(i43) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j43) and R^(k43) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j43) and R^(k43) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R^(Z) is selected from R⁵ and NR⁵R^(5Z);

R⁵ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,6-10 membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(5A) substituents;

R^(5Z) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

or, alternatively, R⁵ and R^(5Z), together with the nitrogen atom towhich they are attached, form a 4-7 membered heterocycloalkyl ring,which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5A) substituents;

each R^(5A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a51), SR^(a51), NHOR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51),C(O)NR^(c51)(OR^(a51)), C(O)OR^(a51), OC(O)R^(b51),OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51), NR^(c51)NR^(c51)R^(d51),NR^(a51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),C(═NR^(e51))R^(b51), C(═NR^(e51))NR^(c51)R^(d51),NR^(c51)C(═NR^(e51))NR^(c51)R^(d51), NR^(c51)C(═NR^(e51))R^(b51),NR^(c51)S(O)NR^(c51)R^(d51), NR^(c51)(O)R^(b51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)(═NR^(e51))R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51),S(O)R^(b51), S(O)NR^(c51)R^(d51), S(O)₂R^(b51), S(O)₂NR^(c51)R^(d51),OS(O)(═NR^(e51))R^(b51), OS(O)₂R^(b51), S(O)(═NR^(e51))R^(b51), SF₅,P(O)R^(f51)R^(g51), OP(O)(OR^(h51))(OR^(i51)), P(O)(OR^(h51))(OR^(i51))and BR^(j51)R^(k51), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

or, any R^(c51) and R^(d51) attached to the same N atom, together withthe N atom to which they are attached, form a 4-10 memberedheterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5B) substituents;

each R^(e51) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,6-10 membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;

each R^(f51) and R^(g51) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,6-10 membered aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;

each R^(h51) and R^(i51) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl;

each R^(j51) and R^(k51) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j51) and R^(k51) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(5B) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a52), SR^(a52), NHOR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)NR^(c52)(OR^(a52)), C(O)OR^(a52), OC(O)R^(b52),OC(O)NR^(c52)R^(d52), NR^(e52)R^(d52), NR^(c52)NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), NR^(c52)C(O)OR^(a2), NR^(c52)C(O)NR^(c52)R^(d52),C(═NR^(e52))R^(b52), C(═NR^(e52))NR^(c52)R^(d52),NR^(c52)C(═NR^(e52))NR^(c52)R^(d52), NR^(c52)C(═NR^(e52))R^(b52),NR^(c52)S(O)NR^(c52)R^(d52), NR^(c52)S(O)R^(b52), NR^(c52)S(O)₂R^(b52),NR^(c52)S(O)(═NR^(e52))R^(b52), NR^(c52)S(O)₂NR^(c52)R^(d52),S(O)R^(b52), S(O)NR^(c52)R^(d52), S(O)₂R^(b52), S(O)₂NR^(c52)R^(d52),OS(O)(═NR^(c52))R^(b52), OS(O)₂R^(b52), S(O)(═NR^(c52))R^(b52), SF₅,P(O)R^(f52)R^(g52), OP(O)(OR^(h52))(OR^(i52)), P(O)(OR^(h52))(OR^(i52)),and BR^(j52)R^(k52), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(5C) substituents;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5C) substituents;

or, any R^(c52) and R^(d52) attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(5C) substituents;

each R^(b52) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5C) substituents;

each R^(e52) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f52) and R^(g52) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h52) and R^(i52) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j52) and R^(k52) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j52) and R^(k52) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(5C) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a53), SR^(a53), NHOR^(a53), C(O)R^(b53), C(O)NR^(c53)R^(d53),C(O)NR^(c53)(OR^(a53)), C(O)OR^(a53), OC(O)R^(b53),OC(O)NR^(c53)R^(d53), NR^(c53)R^(d53), NR^(c53)NR^(c53)R^(d53),NR^(c53)C(O)R^(b53), NR^(c53)C(O)OR^(a53), NR^(c53)C(O)NR^(c53)R^(d53),C(═NR^(e53))R^(b53), C(═NR^(e53))NR^(c53)R^(d53),NR^(c53)C(═NR^(e53))NR^(c53)R^(d53), NR^(c53)C(═NR^(e53))R^(b53),NR^(c53)S(O)NR^(c53)R^(d53), NR^(c53)S(O)R^(b53), NR^(c53)S(O)₂R^(b53),NR^(c53)S(O)(═NR^(e53))R^(b53), NR^(c53)S(O)₂NR^(c53)R^(d53),S(O)R^(b53), S(O)NR^(c53)R^(d53), S(O)₂R^(b53), S(O)₂NR^(c53)R^(d53),OS(O)(═NR^(e53))R^(b53), OS(O)₂R^(b53), S(O)(═NR^(e53))R^(b53), SF₅,P(O)R^(f53)R^(g53), OP(O)(OR^(h53))(OR^(i53)), P(O)(OR^(h53))(OR^(i53)),and BR^(j53)R^(k53), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(G) substituents;

each R^(a53), R^(c53) and R^(d53) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents;

or, any R^(c53) and R^(d53) attached to the same N atom, together withthe N atom to which they are attached, form a 4-7 memberedheterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents;

each R^(b53) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(G) substituents;

each R^(e53) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f53) and R^(g53) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h53) and R^(i53) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j53) and R^(k53) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j53) and R^(k53) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R⁶ is independently selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, OH, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, cyano-C₁₋₄ alkyl, HO—C₁₋₄alkyl, C₁₋₃ alkoxy-C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;

R⁷ is selected from H, D, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, OH, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃alkylamino, di(C₁₋₃ alkyl)amino, cyano-C₁₋₄ alkyl, HO—C₁₋₄ alkyl, C₁₋₃alkoxy-C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; and

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments, R¹ is H, halo, CN, C₁₋₃ alkyl, or C₁₋₃ haloalkyl.

In some embodiments, R¹ is F, Cl, Br, CN, CF₃, CHF₂, CH₂F, CH₂CF₃, orCH₂CHF₂.

In some embodiments, R¹ is CN or C₁₋₃ haloalkyl.

In some embodiments, R¹ is CN or CF₃.

In some embodiments, R¹ is CF₃.

In some embodiments, R¹ is CN.

In some embodiments, R¹ is halo, CN, or C₁₋₃ haloalkyl.

In some embodiments, R¹ is Cl, CN, or CF₃.

In some embodiments, R⁷ is H, halo, CN, C₁₋₂ alkyl, or C₁₋₂haloalkyl.

In some embodiments, R⁷ is H, halo, or CN.

In some embodiments, R⁷ is H.

In some embodiments, Ring moiety A is 4-10 membered heterocycloalkyl,wherein said heterocycloalkyl does not comprise an aromatic ring.

In some embodiments, Ring moiety A is monocyclic 4-7 memberedheterocycloalkyl.

In some embodiments, Ring moiety A is an azetidine ring, a pyrrolidinering, a piperidine ring, or an azepane ring.

In some embodiments, Ring moiety A is azetidin-3-yl, piperidin-3-yl, orpiperidin-4-yl.

In some embodiments, Ring moiety A is piperidin-4-yl.

In some embodiments, n is 0, 1, or 2.

In some embodiments, n is 0 or 1.

In some embodiments, n is 0.

In some embodiments, each R⁶ is independently H, halo, C₁₋₃ alkyl, orC₁₋₃ haloalkyl.

In some embodiments, each R⁶ is selected from H, halo, or C₁₋₃haloalkyl.

In some embodiments, each R⁶ is independently H, halo, or methyl.

In some embodiments, each R⁶ is H.

In some embodiments, each R⁶ is H, F, or CH₃.

In some embodiments, each R⁶ is F or CH₃.

In some embodiments, R^(Z) is NR⁵R^(5Z).

In some embodiments, R^(5Z) is H or methyl.

In some embodiments, R^(Z) is R⁵.

In some embodiments, R^(Z) is N(CH₃)₂, NH(CH₃), or NH(cyclopropyl).

In some embodiments, R⁵ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1,2, or 3 independently selected R^(5A) substituents.

In some embodiments, R⁵ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, and 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, or 3 independently selected R^(5A)substituents.

In some embodiments, R⁵ is selected from C₁₋₃ alkyl, C₃₋₆ cycloalkyl,and 5-6 membered heteroaryl; wherein said C₁₋₃ alkyl, C₃₋₇ cycloalkyl,and 5-6 membered heteroaryl are each optionally substituted by 1 or 2independently selected R^(5A) substituents.

In some embodiments, R⁵ is methyl, cyclopropyl, or imidazolyl, each ofwhich is optionally substituted by 1, 2, or 3 independently selectedR^(5A) substituents.

In some embodiments, R⁵ is methyl, cyclopropyl, or2-methylimidazol-4-yl.

In some embodiments, R⁵ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is optionallysubstituted by 1, 2, or 3 independently selected R^(5A) substituents.

In some embodiments, R⁵ is methyl, ethyl, cyclopropyl, imidazolyl,pyrazolyl, pyridinyl, and pyrimidinyl, each of which is optionallysubstituted by 1, 2, or 3 independently selected R^(5A) substituents.

In some embodiments, R⁵ is methyl, ethyl, cyclopropyl, imidazol-4-yl,pyrazol-3-yl, pyrazol-4-yl, pyridin-2-yl, or pyrimidin-4-yl, each ofwhich is optionally substituted by 1, 2, or 3 independently selectedR^(5A) substituents.

In some embodiments:

each R^(5A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a51), SR^(a51), NHOR^(a51),C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)OR^(a51), OC(O)R^(b51),OC(O)NR^(c51)R^(d51), NR^(c51)R^(c51), NR^(c51)C(O)R^(b51),NR^(c51)(O)OR^(c51), NR^(c51)C(O)NR^(c51)R^(d51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), and S(O)₂NR^(c51)R^(d51),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5C) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents;

each R^(5B) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a52), SR^(a52), NHOR^(a2),C(O)R^(b52), C(O)NR^(c52)R^(d52), C(O)OR^(a52), OC(O)R^(b52),OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52), NR^(c52)C(O)R^(b52),NR^(c52)C(O)OR^(a52), NR^(c52)C(O)NR^(c52)R^(d52), NR^(c52)S(O)₂R^(b52),NR^(c52)S(O)₂NR^(c52)R^(d52)S(O)₂R^(b52), and S(O)₂NR^(c52)R^(d52),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5C) substituents;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5C) substituents;

each R^(b52) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5C) substituents; and

each R^(5C) is independently selected from H, halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments:

each R^(5A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a51), SR^(a51), NHOR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51),C(O)OR^(a51), OC(O)R^(b51), OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),NR^(c51)S(O)₂R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)₂R^(b51), andS(O)₂NR^(c51)R^(d51), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(5B) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(5B) substituents;

each R^(b51) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, or 3 independentlyselected R^(5B) substituents; and

each R^(5B) is independently selected from H, halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments:

each R^(5A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₄ cycloalkyl, OR^(a51), and NR^(c51)R^(d51), wherein saidC₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl are each optionallysubstituted with 1 or 2 independently selected R^(5B) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and

each R^(5B) is independently selected from H, halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments:

each R^(5A) is independently selected from H, halo, CN, C₁₋₃ alkyl, C₁₋₃haloalkyl, and NR^(c51)R^(d51); and

each R^(c51) and R^(d51) is independently selected from H and C₁₋₃alkyl.

In some embodiments, each R^(5A) is independently selected from CH₃ andNH₂.

In some embodiments, R², R³, and R⁴ are defined as in Group (a).

In some embodiments, R³ is H, halo, CN, C₁₋₃ alkyl, or C₁₋₃ haloalkyl.

In some embodiments, R³ is H, F, Cl, Br, CN, CH₃, CH₂CH₃, CF₃, CHF₂,CH₂F, CH₂CF₃, or CH₂CHF₂.

In some embodiments, R³ is H, F, Cl, Br, CN, or CH₃.

In some embodiments, R³ is H, halo, CN, C₁₋₃ alkyl, or C₁₋₃ haloalkyl.

In some embodiments, R³ is H, Cl, Br, CN, or CH₃.

In some embodiments, R² is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,cyano-C₁₋₄ alkyl, HO—C₁₋₄ alkyl, or C₁₋₃ alkoxy-C₁₋₄ alkyl.

In some embodiments, R² is H, halo, C₁₋₄ alkyl, or HO—C₁₋₄ alkyl.

In some embodiments, R² is H, Cl, methyl, or isobutyl, wherein saidmethyl and isobutyl are each optionally substituted with 1 OH group.

In some embodiments, R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 6-10 membered aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, 6-10 memberedaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(4A) substituents.

In some embodiments, R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1,2, 3, or 4 independently selected R^(4A) substituents.

In some embodiments, R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, and C₃₋₇ cycloalkyl-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, and C₃₋₇ cycloalkyl-C₁₋₄ alkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(4A)substituents.

In some embodiments, R⁴ is selected from H, methyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, isobutyl, cyclopropylmethyl, phenyl, pyridinyl,and tetrahydropyran; wherein said methyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, isobutyl, cyclopropylmethyl, phenyl, pyridinyl,and tetrahydropyran are each optionally substituted by 1 or 2 R^(4A)substituents independently selected from F, Cl, CN, OH, CH₃, CF₃,CH₃NHCH₂, CH₃C(O)NH, NH₂, and CNCH₂.

In some embodiments, R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-9 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, 4-9 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-9 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2,or 3 independently selected R^(4A) substituents.

In some embodiments, R⁴ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-9 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, 4-9 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-9 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2,or 3 independently selected R^(4A) substituents.

In some embodiments, R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,phenyl, tetrahydropyranyl, pyridyl, pyrazolyl, isobenzofuran-1(3H)-one,and cyclopropylmethyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl,tetrahydropyranyl, pyridyl, pyrazolyl, isobenzofuran-1(3H)-one, andcyclopropylmethyl are each optionally substituted by 1, 2, or 3independently selected R^(4A) substituents.

In some embodiments:

each R^(4A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a41), SR^(a41), NHOR^(a41),C(O)R^(b41), C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(c41), and S(O)₂NR^(c41)R^(d41),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

each R^(b41) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4B) substituents;

each R^(4B) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a42), SR^(a42), NHOR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)₂R^(b42), and S(O)₂NR^(c42)R^(d42),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4C) substituents;

each R^(b42) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4C) substituents; and

each R^(4C) is independently selected from H, halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments:

each R^(4A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),NR^(c41)S(O)₂R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(c41), andS(O)₂NR^(c41)R^(d41), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4B) substituents;

each R^(b41) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, or 3 independentlyselected R^(4B) substituents; and

each R^(4B) is independently selected from H, halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments:

each R^(4A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₄ cycloalkyl, OR^(a41), SR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41),NR^(c41)R^(d41), NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41),NR^(c41)C(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41),wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl are eachoptionally substituted with 1, 2, or 3 independently selected R^(4B)substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, and C₁₋₆haloalkyl are optionally substituted with 1 or 2 independently selectedR^(4B) substituents;

each R^(b41) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, which are each optionally substituted with 1 or 2independently selected R^(4B) substituents; and

each R^(4B) is independently selected from H, halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments, each R^(4A) is independently selected from H, halo,CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₄ cycloalkyl, OR^(a41), andNR^(c41)C(O)R^(b41), NR^(c41)R^(d41), wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, and C₃₋₄ cycloalkyl are each optionally substituted with 1 or2 independently selected R^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

each R^(b41) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; and

each R^(4B) is independently selected from H, halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments:

each R^(4A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)OR^(a41), OC(O)R^(b41) OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b4), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),NR^(c41)S(O)₂R^(c41), NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(b41), andS(O)₂NR^(c41)R^(d41), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4B) substituents;

each R^(b41) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, or 3 independentlyselected R^(4B) substituents;

each R^(4B) is independently selected from H, D, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a42), SR^(a42), NHOR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42),C(O)OR^(a42), OC(O)R^(b42), OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42),NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42),NR^(c42)S(O)₂R^(b42), NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)₂R^(b42), andS(O)₂NR^(c42)R^(d42), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4C) substituents;

each R^(b42) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, or 3 independentlyselected R^(4C) substituents; and

each R^(4C) is independently selected from H, D, halo, CN, OH, C₁₋₃alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments:

each R^(4A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a41), C(O)NR^(c41)R^(d41), NR^(c41)R^(d41), andNR^(c41)C(O)R^(b41), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H andC₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R^(4B) substituents;

each R^(b41) is independently selected from C₁₋₆ alkyl, which isoptionally substituted with 1, 2, or 3 independently selected R^(4B)substituents;

each R^(4B) is independently selected from H, D, halo, CN, C₁₋₆ alkyl,4-7 membered heterocycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, OR^(a42),NR^(c42)R^(d42) and NR^(c42)C(O)R^(b42), wherein said C₁₋₆ alkyl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, or3 independently selected R^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, and C₃₋₇ cycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,and C₃₋₇ cycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R^(4C) substituents;

each R^(b42) is independently selected from C₁₋₆ alkyl, which isoptionally substituted with 1, 2, or 3 independently selected R^(4C)substituents; and

each R^(4C) is independently selected from D, CN, OH, and C₁₋₃ alkyl.

In some embodiments (Embodiment A):

n is 0, 1, or 2;

Ring moiety A is an azetidine ring, a pyrrolidine ring, a piperidinering, or an azepane ring;

R¹ is H, halo, CN, C₁₋₃ alkyl, or C₁₋₃ haloalkyl;

R² is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, cyano-C₁₋₄ alkyl, HO—C₁₋₄alkyl, or C₁₋₃ alkoxy-C₁₋₄ alkyl;

R³ is H, halo, CN, C₁₋₃ alkyl, or C₁₋₃ haloalkyl;

R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1,2, 3, or 4 independently selected R^(4A) substituents;

each R^(4A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₄ cycloalkyl, OR^(a41), SR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)OR^(a41), OC(O)R^(b41), OC(O)NR^(c41)R^(d41),NR^(c41)R^(d41), NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41),NR^(c41)C(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41),wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl are eachoptionally substituted with 1, 2, or 3 independently selected R^(4B)substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, and C₁₋₆haloalkyl are optionally substituted with 1 or 2 independently selectedR^(4B) substituents;

each R^(b41) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, which are each optionally substituted with 1 or 2independently selected R^(4B) substituents;

each R^(4B) is independently selected from H, halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

R^(Z) is R⁵;

R⁵ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1,2, or 3 independently selected R^(5A) substituents;

each R^(5A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₄ cycloalkyl, OR^(a51), and NR^(c51)R^(d51), wherein saidC₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl are each optionallysubstituted with 1 or 2 independently selected R^(5B) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

each R^(5B) is independently selected from H, halo, CN, OH, C₁₋₃ alkyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino;

each R⁶ is independently H, halo, C₁₋₃ alkyl, or C₁₋₃ haloalkyl; and

R⁷ is H.

In some embodiments (Embodiment B):

n is 0;

Ring moiety A is a piperidine ring;

R¹ is H;

R² is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, cyano-C₁₋₄ alkyl, HO—C₁₋₄alkyl, or C₁₋₃ alkoxy-C₁₋₄ alkyl;

R³ is H, CN, halo, CH₃, or CF₃;

R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, 4-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, and C₃₋₆ cycloalkyl-C₁₋₄alkyl; wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl,4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, and C₃₋₆cycloalkyl-C₁₋₄ alkyl are each optionally substituted by 1 or 2independently selected R^(4A) substituents;

each R^(4A) is independently selected from H, halo, CN, C₁₋₃ alkyl, C₁₋₃haloalkyl, OR^(a41), NR^(c41)R^(d41), and NR^(c41)C(O)R^(b41), whereinsaid C₁₋₃ alkyl is optionally substituted with 1 R^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H andC₁₋₃ alkyl;

each R^(b41) is independently selected from C₁₋₃ alkyl;

each R^(4B) is independently selected from H, CN, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino;

R^(Z) is R⁵;

R⁵ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or 5-6 membered heteroaryl, whereinsaid 5-6 membered heteroaryl is optionally substituted by 1 R^(5A)substituents;

each R^(5A) is independently selected from H and C₁₋₆ alkyl;

each R⁶ is H; and

R⁷ is H.

In some embodiments (Embodiment C):

n is 0 or 1;

Ring moiety A is a piperidine ring;

R¹ is halo, CN, C₁₋₃ alkyl, or C₁₋₃ haloalkyl;

R² is H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or HO—C₁₋₆ alkyl;

R³ is H, halo, CN, C₁₋₃ alkyl, or C₁₋₃ haloalkyl;

R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, 4-9 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-9 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-9 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, or 3 independently selected R^(4A)substituents;

each R^(4A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)OR^(a41), OC(O)R^(b41) OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),NR^(c41)S(O)₂R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)₂R^(b41), andS(O)₂NR^(c41)R^(d41), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4B) substituents;

each R^(b41) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, or 3 independentlyselected R^(4B) substituents;

each R^(4B) is independently selected from H, D, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a42), SR^(a42), NHOR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42),C(O)OR^(a42), OC(O)R^(b42) OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42),NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42),NR^(c42)S(O)₂R^(b42), NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)₂R^(b42), andS(O)₂NR^(c42)R^(d42), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4C) substituents;

each R^(b42) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, or 3 independentlyselected R^(4C) substituents;

each R^(4C) is independently selected from H, D, halo, CN, OH, C₁₋₃alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino;

R^(Z) is NR⁵R^(5Z) or R⁵;

R^(5Z) is H or methyl;

R⁵ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1,2, or 3 independently selected R^(5A) substituents;

each R^(5A) is independently selected from H, halo, CN, C₁₋₃ alkyl, C₁₋₃haloalkyl, and NR^(c51)R^(d51);

each R^(c51) and R^(d51) is independently selected from H and C₁₋₃alkyl;

each R⁶ is independently H, halo, C₁₋₃ alkyl, or C₁₋₃ haloalkyl; and

R⁷ is H.

In some embodiments (Embodiment D):

n is 0 or 1;

Ring moiety A is a piperidine ring;

R¹ is halo, CN, C₁₋₃ alkyl, or C₁₋₃ haloalkyl;

R² is H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or HO—C₁₋₆ alkyl;

R³ is H, halo, CN, C₁₋₃ alkyl, or C₁₋₃ haloalkyl;

R⁴ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, 4-9 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-9 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-9 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, or 3 independently selected R^(4A)substituents;

each R^(4A) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a41), C(O)NR^(c41)R^(d41), NR^(c41)R^(d41), andNR^(c41)C(O)R^(b41), wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H andC₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R^(4B) substituents;

each R^(b41) is independently selected from C₁₋₆ alkyl, which isoptionally substituted with 1, 2, or 3 independently selected R^(4B)substituents;

each R^(4B) is independently selected from H, D, halo, CN, C₁₋₆ alkyl,4-7 membered heterocycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, OR^(a42),NR^(c42)R^(d42) and NR^(c42)C(O)R^(b42), wherein said C₁₋₆ alkyl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, or3 independently selected R^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, and C₃₋₇ cycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,and C₃₋₇ cycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R^(4C) substituents;

each R^(b42) is independently selected from C₁₋₆ alkyl, which isoptionally substituted with 1, 2, or 3 independently selected R^(4C)substituents;

each R^(4C) is independently selected from D, CN, OH, and C₁₋₃ alkyl;

R^(Z) is NR⁵R^(5Z) or R⁵;

R^(5Z) is H or methyl;

R⁵ is selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and 5-6 memberedheteroaryl, each of which is optionally substituted by 1, 2, or 3independently selected R^(5A) substituents;

each R^(5A) is independently selected from CH₃ and NH₂;

each R⁶ is selected from H, halo, or C₁₋₃ haloalkyl; and

R⁷ is H.

In some embodiments, the compound is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IIa):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

X is a bond, CH₂, or CH₂CH₂; and

Y is a bond or CH₂.

In some embodiments, the compound is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IVa):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein:

X is a bond, CH₂, or CH₂CH₂; and

Y is a bond or CH₂.

Formulas (I), (II), (IIa), (III), (IV), (IVa), and (V) can be combinedwith any of the preceding embodiments, more preferably, Embodiment A orEmbodiment B, or most preferably, Embodiment C or Embodiment D.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “phenyl”,“cycloalkyl”, “heterocycloalkyl”, or “heteroaryl” substituents or “—C₁₋₄alkyl-” and “alkylene” linking groups, as described herein, areoptionally replaced by deuterium atoms.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, divalent linkingsubstituents are described. Unless otherwise specified, it isspecifically intended that each divalent linking substituent includeboth the forward and backward forms of the linking substituent. Forexample, —NR(CR′R″)_(n)— includes both —NR(CR′R″)_(n)— and—(CR′R″)_(n)NR—. Where the structure clearly requires a linking group,the Markush variables listed for that group are understood to be linkinggroups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency, that the designated atom's normalvalency is not exceeded, and that the substitution results in a stablecompound.

As used herein, the term “independently selected from” means that eachoccurrence of a variable or substituent are independently selected ateach occurrence from the applicable list.

As used herein, the phrase “each ‘variable’ is independently selectedfrom” means substantially the same as wherein “at each occurrence‘variable’ is selected from.”

When any variable (e.g., R^(G)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 1, 2, 3, or 4 R^(G),then said group may optionally be substituted with up to four R^(G)groups and R^(G) at each occurrence is selected independently from thedefinition of R^(G).

In some embodiments, when an optionally multiple substituent isdesignated in the form:

then it is to be understood that substituent R can occur p number oftimes on the ring, and R can be a different moiety at each occurrence.It is to be understood that each R group may replace any hydrogen atomattached to a ring atom, including one or both of the (CH₂)_(n) hydrogenatoms. Further, in the above example, should the variable Q be definedto include hydrogens, such as when Q is said to be CH₂, NH, etc., anyfloating substituent such as R in the above example, can replace ahydrogen of the Q variable as well as a hydrogen in any othernon-variable component of the ring.

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₃, C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr), n-butyl,tert-butyl, isobutyl, sec-butyl; higher homologs such as2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl,and the like. In some embodiments, the alkyl group contains from 1 to 6carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, theterm “C_(n-m) alkoxy”, employed alone or in combination with otherterms, refers to a group of formula-O-alkyl, wherein the alkyl group hasn to m carbons. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g.,n-butoxy and tert-butoxy), and the like. In some embodiments, the alkylgroup has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2 fused rings). The term “C_(n-m)aryl” refers to an aryl group having from n to m ring carbon atoms. Arylgroups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl,indanyl, indenyl, and the like. In some embodiments, the aryl group has6 to 14 or 6 to 10 carbon atoms. In some embodiments, the aryl group isphenyl or naphthyl. In some embodiments, the aryl is phenyl.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments,halo is F, Cl, or Br. In some embodiments, halo is F or Cl. In someembodiments, halo is F. In some embodiments, halo is Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. Example haloalkoxy groupsinclude OCF₃ and OCHF₂. In some embodiments, the haloalkoxy group isfluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group of thehaloalkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkylgroups include CF₃, C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like.

As used herein, the term “C_(n-m) fluoroalkyl” refers to an alkyl grouphaving from one fluoro atom to 2s+1 fluoro atoms, where “s” is thenumber of carbon atoms in the alkyl group, wherein the alkyl group has nto m carbon atoms. In some embodiments, the alkyl group of thefluoroalkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examplefluoroalkyl groups include CF₃, C₂F₅, CHF₂, CH₂F, and the like.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group of the alkylamino has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group of the alkoxycarbonyl has 1 to 6, 1to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group of the alkylcarbonyl has 1 to 6, 1to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group of the alkylcarbonylaminohas 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkoxycarbonylamino” refers to a groupof formula —NHC(O)O(C_(n-m) alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group of thealkoxycarbonylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group of the alkylsulfonylaminohas 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group of the alkylaminosulfonylhas 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group of thedialkylaminosulfonyl has, independently, 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group of thealkylaminosulfonylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup of the dialkylaminosulfonylamino has, independently, 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group of thealkylaminocarbonylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup of the dialkylaminocarbonylamino has, independently, 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group of the alkylcarbamyl has 1to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group of the alkylthio has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group of the alkylsulfinyl has 1 to 6, 1to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group of the alkylsulfonyl has 1 to 6, 1to 4, or 1 to 3 carbon atoms.

As used herein, the term “cyano-C_(n-m) alkyl” refers to a group offormula —(C_(n-m) alkylene)-CN, wherein the alkylene group has n to mcarbon atoms. As used herein, the term “cyano-C₁₋₆ alkyl” refers to agroup of formula —(C₁₋₆ alkylene)-CN. As used herein, the term“cyano-C₁₋₃ alkyl” refers to a group of formula —(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C_(n-m) alkyl” refers to a group of formulaC_(n-m) alkylene)-OH, wherein the alkylene group has n to m carbonatoms. As used herein, the term “HO—C₁₋₃ alkyl” refers to a group offormula —(C₁₋₃ alkylene)-OH.

As used herein, the term “C_(n-m) alkoxy-C_(o-p) alkyl” refers to agroup of formula —(C_(n-m) alkylene)-O(C_(o-p) alkyl), wherein thealkylene group has n to m carbon atoms and the alkyl group has o to pcarbon atoms. As used herein, the term “C₁₋₆ alkoxy-C₁₋₆ alkyl” refersto a group of formula —(C₁₋₆ alkylene)-O(C₁₋₆ alkyl). As used herein,the term “C₁₋₃ alkoxy-C₁₋₃ alkyl” refers to a group of formula —(C₁₋₃alkylene)-O(C₁₋₃ alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup of the dialkylamino independently has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup of the dialkylcarbamyl independently has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyloxy” is a group offormula —OC(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group of the alkylcarbonyloxy has 1 to 6,1 to 4, or 1 to 3 carbon atoms.

As used herein, “aminocarbonyloxy” is a group of formula —OC(O)—NH₂.

As used herein, “C_(n-m) alkylaminocarbonyloxy” is a group of formula—OC(O)—NH— alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group of the alkylaminocarbonyloxy has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “di(C_(n-m)alkyl)aminocarbonyloxy” is a group of formula—OC(O)—N(alkyl)₂, wherein each alkyl group has, independently, n to mcarbon atoms. In some embodiments, each alkyl group of thedialkylaminocarbonyloxy independently has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein “C_(n-m) alkoxycarbonylamino” refers to a group offormula —NHC(O)—O-alkyl, wherein the alkyl group has n to m carbonatoms.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups,spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group).Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of cyclopentane, cyclohexane,and the like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13 or 14 ring-forming carbons (i.e., C₃₋₁₄). In someembodiments, cycloalkyl is C₃₋₁₄ cycloalkyl, wherein 1, 2, 3, or 4ring-forming carbon atoms of said C₃₋₁₄ cycloalkyl can be optionallysubstituted by one or more oxo or sulfido. In some embodiments, thecycloalkyl is a C₃₋₁₀ monocyclic or bicyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₃₋₇ monocyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₄₋₇ monocyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₄₋₁₄ spirocycle or bridged cycloalkyl(e.g., a bridged bicycloalkyl group). Example cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, cubane, adamantane,bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g.,having 2, 3, or 4 fused rings) aromatic heterocycle having at least oneheteroatom ring member selected from N, O, S and B. In some embodiments,the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring membersindependently selected from N, O, S and B. In some embodiments, anyring-forming N in a heteroaryl moiety can be an N-oxide. In someembodiments, the heteroaryl is a 5-14 membered monocyclic or bicyclicheteroaryl having 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, O, and S. In some embodiments, the heteroaryl is a 5-10membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4heteroatom ring members independently selected from N, O, and S. In someembodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2heteroatom ring members independently selected from N, O, S and B. Insome embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1or 2 heteroatom ring members independently selected from N, O, and S. Insome embodiments, the heteroaryl group contains 3 to 14, 3 to 10, 4 to14, 4 to 10, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments,the heteroaryl group contains 5 to 14, 5 to 10, or 5 to 6 ring-formingatoms. In some embodiments, the heteroaryl group has 1 to 4 ring-formingheteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-formingheteroatoms or 1 ring-forming heteroatom. When the heteroaryl groupcontains more than one heteroatom ring member, the heteroatoms may bethe same or different. Example heteroaryl groups include, but are notlimited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, furyl, thienyl, triazolyl (e.g., 1,2,3-triazolyl,1,2,4-triazolyl, 1,3,4-triazolyl), tetrazolyl, thiadiazolyl (e.g.,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), quinolinyl,isoquinolinyl, indolyl, benzothienyl, benzofuranyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, purinyl, triazinyl, thieno[3,2-b]pyridinyl,imidazo[1,2-a]pyridinyl, 1,5-naphthyridinyl,1H-pyrazolo[4,3-b]pyridinyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), 1,2-dihydro-1,2-azoborinyl, andthe like. In some embodiments, heteroaryl is independently selected fromimidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxazolyl,oxadiazolyl, isoxazolyl, isothiazolyl, furyl, thienyl, pyrimidinyl,pyridyl, pyrazinyl, pyridazinyl, quinoxalinyl, and quinolinyl. In someembodiments, heteroaryl is independently selected from imidazolyl,pyrazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridyl, quinoxalinyl,and quinolinyl.

As used herein, “heterocycloalkyl” refers to monocyclic or polycyclicheterocycles having at least one non-aromatic ring (saturated orpartially unsaturated ring), wherein one or more of the ring-formingcarbon atoms of the heterocycloalkyl is replaced by a heteroatomselected from N, O, S, and B, and wherein the ring-forming carbon atomsand heteroatoms of the heterocycloalkyl group can be optionallysubstituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), orS(O)₂, etc.). Heterocycloalkyl groups include monocyclic and polycyclic(e.g., having 2 fused rings) systems. Included in heterocycloalkyl aremonocyclic and polycyclic 4-14, 4-12, 3-10-, 4-10-, 3-7-, 4-7-, and5-6-membered heterocycloalkyl groups. Heterocycloalkyl groups can alsoinclude spirocycles and bridged rings (e.g., a 5-14 membered bridgedbiheterocycloalkyl ring having one or more of the ring-forming carbonatoms replaced by a heteroatom independently selected from N, O, S, andB). The heterocycloalkyl group can be attached through a ring-formingcarbon atom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the non-aromatic heterocyclic ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. In some embodiments, the heterocycloalkyl group contains3 to 14 ring-forming atoms, 4 to 14 ring-forming atoms, 3 to 10ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-formingatoms, 4 to 7 ring-forming atoms, 4 to 6 ring-forming atoms or 5 to 6ring-forming atoms. In some embodiments, the heterocycloalkyl group has1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1heteroatom.

In some embodiments, the heterocycloalkyl is a 4-14 membered monocyclic,bicyclic, or tricyclic heterocycloalkyl having 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S,wherein 1, 2, 3, or 4 ring-forming carbon or heteroatoms can beoptionally substituted by one or more oxo or sulfido. In someembodiments, the heterocycloalkyl is a 4-10 membered monocyclic,bicyclic, or tricyclic heterocycloalkyl having 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S,wherein 1, 2, 3, or 4 ring-forming carbon or heteroatoms can beoptionally substituted by one or more oxo or sulfido. In someembodiments, the heterocycloalkyl is a 4-7 membered monocyclicheterocycloalkyl having 1 or 2 ring-forming heteroatoms independentlyselected from N, O, and S, and wherein 1, 2 or 3 ring-forming carbon orheteroatoms can be optionally substituted by one or more oxo or sulfido.In some embodiments, the heterocycloalkyl is a monocyclic 4-6 memberedheterocycloalkyl having 1 or 2 heteroatoms independently selected fromN, O, S, and B and having one or more oxidized ring members.

Example heterocycloalkyl groups include pyrrolidin-2-one,1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl,morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, oxo-azetidinyl, oxo-imidazolidinyl,oxopyrrolidinyl, oxo-oxazolidinyl, benzazapene,1,2,3,4-tetrahydroisoquinoline, azabicyclo[3.1.0]hexanyl,diazabicyclo[3.1.0]hexanyl, oxabicyclo[2.1.1]hexanyl,azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl,azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl,azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl,oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl,diazaadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl,diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl,azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl,azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl,diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl,diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxa-diazaspiro[4.4]nonanyl, and the like. In some embodiments,heterocycloalkyl is independently selected from azetidinyl,pyrrolidinyl, piperidinyl, morpholino, piperazinyl, tetrahydrofuranyl,tetrahydropyranyl, imidazolidinyl, isobenzofuran-1(3H)-one,oxo-azetidinyl, oxo-imidazolidinyl, oxopyrrolidinyl, oxo-oxazolidinyl,oxopiperidinyl, azabicyclo[2.2.2]octanyl, azabicyclo[2.2.1]heptanyl,azaspiro[3.3]heptanyl, diazaspiro[3.4]nonanyl,hexahydropyrrolo[1,2-a]pyrazinyl, oxaazabicyclo[2.2.1]heptanyl,oxaazabicyclo[3.1.1]heptanyl, oxaazabicyclo[3.2.1]octanyl, andoxaazabicyclo[2.2.2]octanyl.

As used herein, “C_(o-p) cycloalkyl-C_(n-m) alkyl-” refers to a group offormula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbonatoms and the alkylene linking group has n to m carbon atoms.

As used herein “C_(o-p) aryl-C_(n-m) alkyl-” refers to a group offormula aryl-alkylene-, wherein the aryl has o to p carbon ring membersand the alkylene linking group has n to m carbon atoms.

As used herein, “heteroaryl-C_(n-m) alkyl-” refers to a group of formulaheteroaryl-alkylene-, wherein alkylene linking group has n to m carbonatoms.

As used herein “heterocycloalkyl-C_(n-m) alkyl-” refers to a group offormula heterocycloalkyl-alkylene-, wherein alkylene linking group has nto m carbon atoms.

As used herein, the term “alkylene” refers a divalent straight chain orbranched alkyl linking group. Examples of “alkylene groups” includemethylene, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl,propan-1,2-diyl, propan-1,1-diyl and the like.

As used herein, the term “alkenylene” refers a divalent straight chainor branched alkenyl linking group. Examples of “alkenylene groups”include ethen-1,1-diyl, ethen-1,2-diyl, propen-1,3-diyl,2-buten-1,4-diyl, 3-penten-1,5-diyl, 3-hexen-1,6-diyl, 3-hexen-1,5-diyl,and the like.

As used herein, the term “alkynylene” refers a divalent straight chainor branched alkynyl linking group. Examples of “alkynylene groups”include propyn-1,3-diyl, 2-butyn-1,4-diyl, 3-pentyn-1,5-diyl,3-hexyn-1,6-diyl, 3-hexyn-1,5-diyl, and the like.

As used herein, an “alkyl linking group” is a bivalent straight chain orbranched alkyl linking group (“alkylene group”). For example, “C_(o-p)cycloalkyl-C_(n-m) alkyl-”, “C_(o-p) aryl-C_(n-m) alkyl-”,“phenyl-C_(n-m) alkyl-”, “heteroaryl-C_(n-m) alkyl-”, and“heterocycloalkyl-C_(n-m) alkyl-” contain alkyl linking groups. Examplesof “alkyl linking groups” or “alkylene groups” include methylene,ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl, propan-1,2-diyl,propan-1,1-diyl and the like.

As used herein, the term “oxo” refers to an oxygen atom (i.e., ═O) as adivalent substituent, forming a carbonyl group when attached to a carbon(e.g., C═O or C(O)), or attached to a nitrogen or sulfur heteroatomforming a nitroso, sulfinyl or sulfonyl group.

As used herein, the term “independently selected from” means that eachoccurrence of a variable or substituent are independently selected ateach occurrence from the applicable list.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration. The Formulas (e.g.,Formula (I), (II), etc.) provided herein include stereoisomers of thecompounds.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such as0-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide-imidic acidpairs, lactam—lactim pairs, enamine—imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present disclosure include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present disclosure can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (ACN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in itsentirety.

Synthesis

As will be appreciated by those skilled in the art, the compoundsprovided herein, including salts and stereoisomers thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as thoseprovided in the Schemes below.

The reactions for preparing compounds described herein can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

The expressions, “ambient temperature” or “room temperature” or “r.t.”as used herein, are understood in the art, and refer generally to atemperature, e.g., a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) and normal phase silicachromatography.

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of formula (I) can be prepared by the general syntheticprocedure illustrated in Scheme 1. In Scheme 1, substituted2,4-dichloropyrimidines of formula 1-1 react with appropriatelysubstituted compounds of formula 1-2 (M=e.g., appropriatelyfunctionalized boron species, i.e., boronic acid pinacol esters, orappropriately functionalized tin species, i.e., tributylstannanes) by asuitable Suzuki or Stille cross-coupling (e.g., in the presence of apalladium catalyst, such as Pd(dppf)Cl₂, Pd(PPh₃)₂C₂, or Pd(PPh₃)₄ and abase such as sodium carbonate) in a suitable solvent (e.g., CH₃CN/H₂O,1,4-dioxane/H₂O, DMF) to provide compounds of formula 1-3. Appropriatelysubstituted compounds of formula 1-3 can then be converted intocompounds of formula (I) by a number of methods, e.g., by nucleophilicaromatic substitution with an appropriate amine nucleophile in asuitable solvent (e.g., DMSO, DMF, 1,4-dioxane) with or without asuitable base (e.g., triethylamine, N,N-diisopropylethylamine, orCs₂CO₃) or acid additive (e.g., a Lewis acid, such as ZnCl₂, or aBrønsted acid, such asp-toluenesulfonic acid), or by a suitable C—Ncross-coupling, including Buchwald-Hartwig amination (e.g., in thepresence of a palladium precatalyst, such as RuPhos Pd G3, and a basesuch as Cs₂CO₃) in a suitable solvent (e.g., 1,4-dioxane).

As shown in Scheme 2, the sequence of reactions can be modified for thelater stage exploration of substitution at positions R², R³, and R⁴. InScheme 2, compounds of formula 2-1 are accessed via the reaction ofappropriately substituted compounds of formula 1-1 with amines offormula 1-4 in the presence of zinc(II) chloride and triethylamine in asuitable solvent (e.g., a mixture of tert-butanol and1,2-dichloroethane). Suzuki cross-coupling (e.g., in the presence of apalladium catalyst, such as Pd(dppf)Cl₂ or Pd(PPh₃)₂C₂, and a base suchas sodium carbonate) or Stille cross-coupling (e.g., in the presence ofa palladium catalyst, such as Pd(PPh₃)₄) of appropriately substitutedcompounds of formula 2-1 with compounds of formula 1-2 (M=e.g.,appropriately functionalized boron species, i.e., boronic acid pinacolesters or appropriately functionalized tin species, i.e.,tributylstannanes) provides compounds of formula (I).

Compounds of formula (I) with a variety of substitutions at position R⁴can be prepared using the processes illustrated in Scheme 3. In Scheme3, Suzuki or Stille cross-coupling of 4-chloropyrimidines of formula 2-1with appropriately substituted imidazoles of formula 3-1 (M=e.g.,appropriately functionalized boron species, i.e., boronic acid pinacolesters or appropriately functionalized tin species, i.e.,tributylstannanes), where PG represents a protecting group (e.g., Boc,SEM, or Tr), followed by protecting group removal provides compounds offormula 3-2. Under certain conditions, the protecting group may beremoved during the Suzuki or Stille coupling to afford 1H-imidazoles offormula 3-2 directly. Alternatively, various protecting groupdeprotection can be accomplished under standard conditions. Compounds offormula 3-2 can then be converted into compounds of formula (I) by avariety of methods. Functionalization of the imidazole nitrogen inappropriately substituted compounds of formula 3-2 may be achieved viareaction with R⁴-LG, where LG represents a leaving group (e.g., halide,mesylate, or triflate), under basic conditions in a suitable solvent(e.g., DMF, THF). In turn, reaction of appropriately substitutedcompounds of formula 3-2 with alcohols of formula R⁴—OH under Mitsunobuconditions furnishes compounds of formula (I). In cases where R⁴ isaryl, appropriately substituted compound of formula 3-2 can be convertedinto N-aryl imidazoles of formula (I) by a variety of methods, includingnucleophilic aromatic substitution with an appropriate aryl halide underbasic conditions (e.g., N,N-diisopropylethylamine, sodium hydride, orCs₂CO₃) in a suitable solvent (e.g., DMSO, DMF, THF), or by a suitablecopper-mediated coupling, e.g., an Ullmann reaction with aryl halides(e.g., in the presence of a copper catalyst, such as copper(I) iodide, aligand, such as trans-N,N′-Dimethylcyclohexane-1,2-diamine,phenanthroline, or 2-hydroxybenzaldehyde oxime, and a base such asCs₂CO₃) in a suitable solvent (e.g., DMSO, DMF, CH₃CN), or a Chan-Lamcoupling with aryl boronic acids (e.g., in the presence of a coppercatalyst, such as copper(II) acetate, and pyridine) in a suitablesolvent (e.g., CH₂Cl₂). An array of functionality at position R⁴ offormula (I) can also be introduced by a nucleophilic conjugate additionreaction with various Michael-like acceptors (e.g., acrylates,acrylonitriles, or nitroalkenes) with or without a basic reactionadditive (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine) in asuitable solvent (e.g., CH₃CN, CH₂Cl₂).

As shown in Scheme 4, substituted imidazoles of formula 4-1 can betreated with a halogenating agent (e.g., N-chlorosuccinimide,N-bromosuccinimide) in a suitable solvent (e.g., CH₃CN, DMF, DCM) toprovide compounds of formula 4-2 (X=e.g., chloro, bromo). Suitablecross-coupling reactions with halogenated imidazoles of formula 4-2 canprovide compounds of formula I.

Substituted imidazoles of formula 5-1 can be directly functionalized atthe R² position as shown in Scheme 5. This can be achieved by palladiummediated C—H activation of the imidazoles of formula 5-1 with aryliodides in the presence of an appropriate catalyst (e.g., Pd(OAc)₂) in asuitable solvent (e.g., DMF) to provide compounds of Formula I.Alternately imidazoles of formula 5-1 can be sequentially treated withexcess lithium reagent (e.g., n-butyllithium) and a variety ofelectrophiles (e.g., alkyl halides, epoxides, carbonyl-containingcompounds, Michael-like acceptors) in an appropriate solvent (e.g., THF,toluene) to deliver R² functionalized imidazoles of Formula I.

As shown in Scheme 6, substituted imidazoles of formula 5-1 can behalogenated with a halogenating agent (e.g., N-chlorosuccinimide,N-bromosuccinimide) in a suitable solvent (e.g., CH₃CN, DMF, DCM) toprovide compounds of formula 6-1 (X=e.g., chloro, bromo). Halogenatedimidazoles of formula 6-1 can then undergo cross-coupling reactions toprovide compounds of formula I.

Methods of Use

Compounds of the present disclosure can inhibit CDK2 and therefore areuseful for treating diseases wherein the underlying pathology is, whollyor partially, mediated by CDK2. Such diseases include cancer and otherdiseases with proliferation disorder. In some embodiments, the presentdisclosure provides treatment of an individual or a patient in vivousing a compound of Formula (I) or a salt thereof such that growth ofcancerous tumors is inhibited. A compound of Formula (I) or of any ofthe formulas as described herein, or a compound as recited in any of theclaims and described herein, or a salt thereof, can be used to inhibitthe growth of cancerous tumors with aberrations that activate the CDK2kinase activity. These include, but are not limited to, disease (e.g.,cancers) that are characterized by amplification or overexpression ofCCNE1 such as ovarian cancer, uterine carcinosarcoma and breast cancerand p27 inactivation such as breast cancer and melanomas. Accordingly,in some embodiments of the methods, the patient has been previouslydetermined to have an amplification of the cyclin E1 (CCNE1) gene and/oran expression level of CCNE1 in a biological sample obtained from thehuman subject that is higher than a control expression level of CCNE1.Alternatively, a compound of Formula (I) or of any of the formulas asdescribed herein, or a compound as recited in any of the claims anddescribed herein, or a salt thereof, can be used in conjunction withother agents or standard cancer treatments, as described below. In oneembodiment, the present disclosure provides a method for inhibitinggrowth of tumor cells in vitro. The method includes contacting the tumorcells in vitro with a compound of Formula (I) or of any of the formulasas described herein, or of a compound as recited in any of the claimsand described herein, or of a salt thereof. In another embodiment, thepresent disclosure provides a method for inhibiting growth of tumorcells with CCNE1 amplification and overexpression in an individual or apatient. The method includes administering to the individual or patientin need thereof a therapeutically effective amount of a compound ofFormula (I) or of any of the formulas as described herein, or of acompound as recited in any of the claims and described herein, or a saltor a stereoisomer thereof.

In some embodiments, provided herein is a method of inhibiting CDK2,comprising contacting the CDK2 with a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. In some embodiments,provided herein is a method of inhibiting CDK2 in a patient, comprisingadministering to the patient a compound of Formula (I) or any of theformulas as described herein, a compound as recited in any of the claimsand described herein, or a salt thereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient (in need thereof), atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. In another embodiment,the cancer is characterized by amplification or overexpression of CCNE1.In some embodiments, the cancer is ovarian cancer or breast cancer,characterized by amplification or overexpression of CCNE1.

In some embodiments, provided herein is a method of treating a diseaseor disorder associated with CDK2 in a patient, comprising administeringto the patient a therapeutically effective amount of a compound ofFormula (I) or any of the formulas as described herein, a compound asrecited in any of the claims and described herein, or a salt thereof. Insome embodiments, the disease or disorder associated with CDK2 isassociated with an amplification of the cyclin E1 (CCNE1) gene and/oroverexpression of CCNE1.

In some embodiments, the disease or disorder associated with CDK2 isN-myc amplified neuroblastoma cells (see Molenaar, et al., Proc NatlAcad Sci USA 106(31): 12968-12973) K-Ras mutant lung cancers (see Hu,S., et al., Mol Cancer Ther, 2015. 14(11): 2576-85, and cancers withFBW7 mutation and CCNE1 overexpression (see Takada, et al., Cancer Res,2017. 77(18): 4881-4893).

In some embodiments, the disease or disorder associated with CDK2 islung squamous cell carcinoma, lung adenocarcinoma, pancreaticadenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma,ovarian serous cystadenocarcinoma, stomach adenocarcinoma, esophagealcarcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

In some embodiments, the disease or disorder associated with CDK2 islung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma,ovarian serous cystadenocarcinoma, or stomach adenocarcinoma.

In some embodiments, the disease or disorder associated with CDK2 is anadenocarcinoma, carcinoma, or cystadenocarcinoma.

In some embodiments, the disease or disorder associated with CDK2 isuterine cancer, ovarian cancer, stomach cancer, esophageal cancer, lungcancer, bladder cancer, pancreatic cancer, or breast cancer.

In some embodiments, the disease or disorder associated with CDK2 is acancer.

In some embodiments, the cancer is characterized by amplification oroverexpression of CCNE1. In some embodiments, the cancer is ovariancancer or breast cancer, characterized by amplification oroverexpression of CCNE1.

In some embodiments, the breast cancer is chemotherapy or radiotherapyresistant breast cancer, endocrine resistant breast cancer, trastuzumabresistant breast cancer, or breast cancer demonstrating primary oracquired resistance to CDK4/6 inhibition. In some embodiments, thebreast cancer is advanced or metastatic breast cancer.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma, BRAFand HSP90 inhibition-resistant melanoma), renal cancer (e.g., clear cellcarcinoma), prostate cancer (e.g., hormone refractory prostateadenocarcinoma), breast cancer, colon cancer, lung cancer (e.g.,non-small cell lung cancer and small cell lung cancer), squamous cellhead and neck cancer, urothelial cancer (e.g., bladder) and cancers withhigh microsatellite instability (MSI^(high)). Additionally, thedisclosure includes refractory or recurrent malignancies whose growthmay be inhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including follicularlymphoma, including relapsed or refractory NHL and recurrentfollicular), Hodgkin lymphoma or multiple myeloma) and combinations ofsaid cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to,cholangiocarcinoma, bile duct cancer, triple negative breast cancer,rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellularcarcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma,neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma,epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinalcancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinalcancer, islet cell cancer, oral cancer, mouth cancer, throat cancer,laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavitycancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer,renal cell carcinoma, salivary gland cancer, sinus cancer, spinalcancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteralcancer.

In some embodiments, the compounds of the present disclosure can be usedto treat sickle cell disease and sickle cell anemia.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), and essential thrombocytosis (ET)),myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma(T-ALL) and multiple myeloma (MM).

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer (SCLC), bronchogenic carcinoma, squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma (pinealoma),glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma,retinoblastoma, congenital tumors), and spinal cord (neurofibroma,meningioma, glioma, sarcoma), as well as neuroblastoma andLhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, Merkelcell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

It is believed that compounds of Formula (I), or any of the embodimentsthereof, may possess satisfactory pharmacological profile and promisingbiopharmaceutical properties, such as toxicological profile, metabolismand pharmacokinetic properties, solubility, and permeability. It will beunderstood that determination of appropriate biopharmaceuticalproperties is within the knowledge of a person skilled in the art, e.g.,determination of cytotoxicity in cells or inhibition of certain targetsor channels to determine potential toxicity.

The terms “individual”, “patient,” and “subject” used interchangeably,refer to any animal, including mammals, preferably mice, rats, otherrodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates,and most preferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

I. Cancer Therapies

Cancer cell growth and survival can be impacted by dysfunction inmultiple signaling pathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well astargeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, and CDK4/6 kinase inhibitors suchas, for example, those described in WO 2006/056399 can be used incombination with the compounds of the present disclosure for treatmentof CDK2-associated diseases, disorders or conditions. Other agents suchas therapeutic antibodies can be used in combination with the compoundsof the present disclosure for treatment of CDK2-associated diseases,disorders or conditions. The one or more additional pharmaceuticalagents can be administered to a patient simultaneously or sequentially.

In some embodiments, the CDK2 inhibitor is administered or used incombination with a BCL2 inhibitor or a CDK4/6 inhibitor.

The compounds as disclosed herein can be used in combination with one ormore other enzyme/protein/receptor inhibitors therapies for thetreatment of diseases, such as cancer and other diseases or disordersdescribed herein. Examples of diseases and indications treatable withcombination therapies include those as described herein.

Examples of cancers include solid tumors and non-solid tumors, such asliquid tumors, and blood cancers. Examples of infections include viralinfections, bacterial infections, fungus infections or parasiteinfections. For example, the compounds of the present disclosure can becombined with one or more inhibitors of the following kinases for thetreatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK4/6, TGF-βR, PKA, PKG,PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR,HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K(alpha, beta, gamma, delta, and multiple or selective), CSF1R, KIT,FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met,PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3,VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn,Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In someembodiments, the compounds of the present disclosure can be combinedwith one or more of the following inhibitors for the treatment of canceror infections. Non-limiting examples of inhibitors that can be combinedwith the compounds of the present disclosure for treatment of cancer andinfections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4,e.g., pemigatinib (INCB54828), INCB62079), an EGFR inhibitor (also knownas ErB-1 or HER-1; e.g., erlotinib, gefitinib, vandetanib, orsimertinib,cetuximab, necitumumab, or panitumumab), a VEGFR inhibitor or pathwayblocker (e.g. bevacizumab, pazopanib, sunitinib, sorafenib, axitinib,regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab,lenvatinib, ziv-aflibercept), a PARP inhibitor (e.g., olaparib,rucaparib, veliparib or niraparib), a JAK inhibitor (JAK1 and/or JAK2,e.g., ruxolitinib or baricitinib; JAK1, e.g., itacitinib (INCB39110),INCB052793, or INCB054707), an IDO inhibitor (e.g., epacadostat, NLG919,or BMS-986205, MK7162), an LSD1 inhibitor (e.g., GSK29979552, INCB59872and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g.,parsaclisib (INCB50465) or INCB50797), a PI3K-gamma inhibitor such asPI3K-gamma selective inhibitor, a Pim inhibitor (e.g., INCB53914), aCSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer;e.g., INCB081776), an adenosine receptor antagonist (e.g., A2a/A2breceptor antagonist), an HPK1 inhibitor, a chemokine receptor inhibitor(e.g., CCR2 or CCR5 inhibitor), a SHP1/2 phosphatase inhibitor, ahistone deacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, anangiogenesis inhibitor, an interleukin receptor inhibitor, bromo andextra terminal family members inhibitors (for example, bromodomaininhibitors or BET inhibitors such as INCB54329 and INCB57643), c-METinhibitors (e.g., capmatinib), an anti-CD19 antibody (e.g.,tafasitamab), an ALK2 inhibitor (e.g., INCB00928); or combinationsthereof.

In some embodiments, the compound or salt described herein isadministered with a PI3Kδ inhibitor. In some embodiments, the compoundor salt described herein is administered with a JAK inhibitor. In someembodiments, the compound or salt described herein is administered witha JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In someembodiments, the compound or salt described herein is administered witha JAK1 inhibitor. In some embodiments, the compound or salt describedherein is administered with a JAK1 inhibitor, which is selective overJAK2.

Example antibodies for use in combination therapy include, but are notlimited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g.,anti-VEGF-A), bevacizumab (AVASTIN™, e.g., anti-VEGF), panitumumab(e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (e.g.,anti-CD20), and antibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present disclosure and are presented as a non-limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™(gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, intron, ara-C,adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine,ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine,6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™(oxaliplatin), pentostatine, vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, goserelin, carboplatin, hydroxyurea, amsacrine,procarbazine, mitotane, mitoxantrone, levamisole, navelbene,anastrazole, letrazole, capecitabine, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan,trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab,C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine,aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1,fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, andMDL-101,731.

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, bispecific ormulti-specific antibody, antibody drug conjugate, adoptive T celltransfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor, PI3KS inhibitor and the like. The compounds can beadministered in combination with one or more anti-cancer drugs, such asa chemotherapeutic agent. Examples of chemotherapeutics include any ofabarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine,bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, busulfanintravenous, busulfan oral, calusterone, capecitabine, carboplatin,carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, andzoledronate.

Additional examples of chemotherapeutics include proteasome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Abl inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Flt-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

Example suitable CDK4/6 inhibitors include palbociclib, ribociclib,trilaciclib, lerociclib, and abemaciclib, and their pharmaceuticallyacceptable salts. Other example suitable CDK4/6 inhibitors includecompounds, and their pharmaceutically acceptable salts, as disclosed inWO 09/085185, WO 12/129344, WO 11/101409, WO 03/062236, WO 10/075074,and WO 12/061156.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic in the treatment of cancer, and mayimprove the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining a CDK2 inhibitor of the present disclosure with anadditional agent.

The agents can be combined with the present compound in a single orcontinuous dosage form, or the agents can be administered simultaneouslyor sequentially as separate dosage forms.

The compounds of the present disclosure can be used in combination withone or more other inhibitors or one or more therapies for the treatmentof infections. Examples of infections include viral infections,bacterial infections, fungus infections or parasite infections.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of thedisclosure where the dexamethasone is administered intermittently asopposed to continuously.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

In some further embodiments, combinations of the compounds of thedisclosure with other therapeutic agents can be administered to apatient prior to, during, and/or after a bone marrow transplant or stemcell transplant. The compounds of the present disclosure can be used incombination with bone marrow transplant for the treatment of a varietyof tumors of hematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self-antigens. Examples ofpathogens for which this therapeutic approach may be particularly usefulinclude pathogens for which there is currently no effective vaccine, orpathogens for which conventional vaccines are less than completelyeffective. These include, but are not limited to, HIV, Hepatitis (A, B,& C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcusaureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limited to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumps virus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

II. Immune-Checkpoint Therapies

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors for the treatment of diseases, suchas cancer or infections. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CBL-B, CD20,CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3Kdelta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1B),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7/8), TIGIT,CD112R, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the immunecheckpoint molecule is a stimulatory checkpoint molecule selected fromCD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, theimmune checkpoint molecule is an inhibitory checkpoint molecule selectedfrom A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3,TIGIT, and VISTA. In some embodiments, the compounds provided herein canbe used in combination with one or more agents selected from KIRinhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4inhibitors and TGFR beta inhibitors.

In some embodiments, the compounds provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, GITR, and CD137 (also known as 4-1B).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-L1monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab,avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab,spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001),camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224,AMP-514/MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736,FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316,CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333,MSB-2311, HLX20, TSR-042, or LY3300054.In some embodiments, theinhibitor of PD-1 or PD-L1 is one disclosed in U.S. Pat. Nos. 7,488,802,7,943,743, 8,008,449, 8,168,757, 8,217, 149, WO 03042402, WO 2008156712,WO 2010089411, WO 2010036959, WO 2011066342, WO 2011159877, WO2011082400, or WO 2011161699, which are each incorporated herein byreference in its entirety.

In some embodiments, the antibody is an anti-PD-1 antibody, e.g., ananti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab,camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224,JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042.In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab,cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, orsintilimab. In some embodiments, the anti-PD-1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab.In some embodiments, the anti-PD-1 antibody is cemiplimab. In someembodiments, the anti-PD-1 antibody is spartalizumab. In someembodiments, the anti-PD-1 antibody is camrelizumab. In someembodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments,the anti-PD-1 antibody is toripalimab. In some embodiments, theanti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1antibody is AB122. In some embodiments, the anti-PD-1 antibody isAMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. Insome embodiments, the anti-PD-1 antibody is BGB-108. In someembodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, theanti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1antibody is LZM009. In some embodiments, the anti-PD-1 antibody isAK105. In some embodiments, the anti-PD-1 antibody is HLX10. In someembodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, theanti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In someembodiments, the anti-PD-1 monoclonal antibody is MGA012. In someembodiments, the anti-PD1 antibody is SHR-1210. Other anti-canceragent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab,utomilumab). In some embodiments, the inhibitor of an immune checkpointmolecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonalantibody. In some embodiments, the anti-PD-L1 monoclonal antibody isatezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736,atezolizumab (MPDL3280A; also known as RG7446), avelumab (MSB0010718C),FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301,BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, theanti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, ortislelizumab. In some embodiments, the anti-PD-L1 antibody isatezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab.In some embodiments, the anti-PD-L1 antibody is durvalumab. In someembodiments, the anti-PD-L1 antibody is tislelizumab. In someembodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments,the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody isKN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In someembodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments,the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1antibody is A167. In some embodiments, the anti-PD-L1 antibody isSTI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. Insome embodiments, the anti-PD-L1 antibody is BGB-A333. In someembodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments,the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1antibody is LY3300054.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule that binds to PD-L1, or a pharmaceutically acceptablesalt thereof. In some embodiments, the inhibitor of an immune checkpointmolecule is a small molecule that binds to and internalizes PD-L1, or apharmaceutically acceptable salt thereof. In some embodiments, theinhibitor of an immune checkpoint molecule is a compound selected fromthose in US 2018/0179201, US 2018/0179197, US 2018/0179179, US2018/0179202, US 2018/0177784, US 2018/0177870, U.S. Ser. No. 16/369,654(filed Mar. 29, 2019), and U.S. Ser. No. 62/688,164, or apharmaceutically acceptable salt thereof, each of which is incorporatedherein by reference in its entirety.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4 and TGFR beta.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftilagimodalpha (IMP321).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isoleclumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT isOMP-31M32.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of VISTA. In some embodiments, the inhibitor of VISTA isJNJ-61610588 or CA-170.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 isenoblituzumab, MGD009, or 8H9.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR. In some embodiments, the inhibitor of KIR islirilumab or IPH4102.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of A2aR. In some embodiments, the inhibitor of A2aR isCPI-444.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-betais trabedersen, galusertinib, or M7824.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PI3K-gamma. In some embodiments, the inhibitor ofPI3K-gamma is IPI-549.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD47. In some embodiments, the inhibitor of CD47 isHu5F9-G4 or TTI-621.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isMEDI9447.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD70. In some embodiments, the inhibitor of CD70 iscusatuzumab or BMS-936561.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7/8, and CD137 (alsoknown as 4-1BB).

In some embodiments, the agonist of CD137 is urelumab. In someembodiments, the agonist of CD137 is utomilumab.

In some embodiments, the agonist of an immune checkpoint molecule is aninhibitor of GITR. In some embodiments, the agonist of GITR is TRX518,MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, orMEDI6469.In some embodiments, the agonist of an immune checkpointmolecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40Lfusion protein. In some embodiments, the anti-OX40 antibody isINCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998,BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein isMEDI6383.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD40. In some embodiments, the agonist of CD40 is CP-870893,ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or ChiLob 7/4.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of ICOS. In some embodiments, the agonist of ICOS isGSK-3359609, JTX-2011, or MEDI-570.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD28. In some embodiments, the agonist of CD28 istheralizumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of TLR7/8. In some embodiments, the agonist of TLR7/8 isMEDI9197.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor. In some embodiments, the bispecificantibody binds to PD-1 and PD-L1. In some embodiments, the bispecificantibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments,the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments,the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the disclosure can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral, or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the disclosure, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the disclosure may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the disclosure can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the disclosure can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), or more, such as about100 to about 500 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

In some embodiments, the compositions of the disclosure contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the disclosure.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentdisclosure can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the disclosure. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the disclosure in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of thedisclosure can be provided in an aqueous physiological buffer solutioncontaining about 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the disclosure can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present disclosure relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating CDK2 in tissue samples,including human, and for identifying CDK2 activators by inhibitionbinding of a labeled compound. Substitution of one or more of the atomsof the compounds of the present disclosure can also be useful ingenerating differentiated ADME (Adsorption, Distribution, Metabolism andExcretion.) Accordingly, the present disclosure includes CDK2 assaysthat contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas —CD₃ being substituted for —CH₃). In some embodiments, alkyl groupsof the disclosed Formulas (e.g., Formula (I)) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. For example, one or more hydrogen atoms in acompound presented herein can be replaced or substituted by deuterium(e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group can be replacedby deuterium atoms, such as —CD₃ being substituted for —CH₃). In someembodiments, the compound includes two or more deuterium atoms. In someembodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 deuteriumatoms. In some embodiments, all of the hydrogen atoms in a compound canbe replaced or substituted by deuterium atoms.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl,heterocycloalkyl, or heteroaryl substituents or —C₁₋₄ alkyl-, alkylene,alkenylene and alkynylene linking groups, as described herein, areoptionally replaced by deuterium atoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas, New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J.Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitutionat one or more metabolism sites may afford one or more of thetherapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro CDK2 labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵S canbe useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I,¹³¹I, ⁷⁵Br, ⁷⁶Br, or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S, and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and one of ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the disclosure can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind and activate CDK2 by monitoring itsconcentration variation when contacting with CDK2, through tracking ofthe labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known toinhibit CDK2 (i.e., standard compound). Accordingly, the ability of atest compound to compete with the standard compound for binding to CDK2directly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, forexample, in the treatment or prevention of CDK2-associated diseases ordisorders (such as, e.g., cancer, an inflammatory disease, acardiovascular disease, or a neurodegenerative disease) which includeone or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thedisclosure. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

Biomarkers and Pharmacodynamics Markers

The disclosure further provides predictive markers (e.g., biomarkers andpharmacodynamic markers, e.g., gene copy number, gene sequence,expression levels, or phosphorylation levels) to identify those humansubjects having, suspected of having, or at risk of developing a diseaseor disorder associated with CDK2 for whom administering a CDK2 inhibitor(“a CDK2 inhibitor” as used herein refers to a compound of thedisclosure, or a pharmaceutically acceptable salt thereof) is likely tobe effective. The disclosure also provides pharmacodynamic markers(e.g., phosphorylation levels) to identify those human subjects having,suspected of having, or at risk of developing a disease or disorderassociated with CDK2 whom are responding to a CDK2 inhibitor.

The methods are based, at least in part, on the discovery that thefunctional status of cyclin dependent kinase inhibitor 2A (“CDKN2A”;also referred to as “p16”) is a biomarker for predicting sensitivity toCDK2-targeting therapies in G1/S-specific cyclin-E1-(“CCNE1-”) amplifiedcells suitable for use in patient stratification. In addition, thepresent invention is based, at least in part, on the discovery that, inCCNE-amplified cell lines, the level of human retinoblastoma associatedprotein (“Rb”) phosphorylation at the serine corresponding to amino acidposition 780 of SEQ ID NO:3 is a pharmacodynamic marker for CDK2activity and is suitable for use in measuring CDK2 enzymatic activity incellular assay or preclinical and clinical applications, such as, e.g.,monitoring the progress of or responsiveness to treatment with a CDK2inhibitor.

CCNE1 and p16

CCNE1 and p16 have been identified in the Examples as genes, incombination, useful in predicting responsiveness (e.g., improvement indisease as evidenced by disease remission/resolution) of a subjecthaving a disease or disorder associated with CDK2 to a CDK2 inhibitor.

p16 (also known as cyclin-dependent kinase inhibitor 2A,cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, andp16-INK4a) acts as a negative regulator of the proliferation of normalcells by interacting with CDK4 and CDK6. p16 is encoded by the cyclindependent kinase inhibitor 2A (“CDKN2A”) gene (GenBank Accession No.NM_000077). The cytogenic location of the CDKN2A gene is 9p21.3, whichis the short (p) arm of chromosome 9 at position 21.3. The molecularlocation of the CDKN2A gene is base pairs 21,967,752 to 21,995,043 onchromosome 9 (Homo sapiens Annotation Release 109, GRCh38.p12). Geneticand epigenetic abnormalities in the gene encoding p16 are believed tolead to escape from senescence and cancer formation (Okamoto et al.,1994, PNAS 91(23):11045-9). Nonlimiting examples of geneticabnormalities in the gene encoding p16 are described in Table 1, below.The amino acid sequence of human p16 is provided below (GenBankAccession No. NP_000068/UniProtKB Accession No. P42771):

(SEQ ID NO: 1)   1 MEPAAGSSME PSADWLATAA ARGRVEEVRA    LLEAGALPNA PNSYGRRPIQ VMMMGSARVA 61 ELLLLHGAEP NCADPATLTR PVHDAAREGF    LDTLVVLHRA GARLDVRDAW GRLPVDLAEE121 LGHRDVARYL RAAAGGTRGS NHARIDAAEG     PSDIPD.

CCNE1 is a cell cycle factor essential for the control of the cell cycleat the G1/S transition (Ohtsubo et al., 1995, Mol. Cell. Biol.15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2, interactingwith CDK2 to form a serine/threonine kinase holoenzyme complex. TheCCNE1 subunit of this holoenzyme complex provides the substratespecificity of the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1is encoded by the cyclin E1 (“CCNE1”) gene (GenBank Accession No.NM_001238). The amino acid sequence of human CCNE1 is provided below(GenBank Accession No. NP_001229/UniProtKB Accession No. P24864):

(SEQ ID NO: 2)   1 mprerrerda kerdtmkedg gaefsarsrk    rkanvtvflq dpdeemakid rtardqcgsq 61 pwdnnavcad pcsliptpdk edddrvypns    tckpriiaps rgsplpvlsw anreevwkim121 lnkektylrd qhfleghpll qpkmrailld    wlmevcevyk lhretfylaq dffdrymatq181 envvktllql igisslfiaa kleeiyppkl    hqfayvtdga csgdeiltme lmimkalkwr241 lspltivswl nvymqvayln dlhevllpqy    pgqifigiae lldlcvldvd clefpygila301 asalyhfsss elmqkvsgyq wcdiencvkw    mvpfamvire tgssklkhfr gvadedahni361 qthrdsldll dkarakkaml seqnrasplp     sglltppqsg kkqssgpema.

The Examples demonstrate CDK2-knockdown inhibits proliferation ofCCNE1-amplified cell lines, but not of CCNE-non-amplified cell lines.Conversely, the Examples show that CDK4/6 inhibition inhibitsproliferation of CCNE-non-amplified cell lines, but not ofCCNE-amplified cell lines. The Examples further demonstrate thatpresence of a normal (e.g., non-mutated or non-deleted) p16 gene isrequired for the observed inhibition of cell proliferation inCCNE1-amplified cells treated with a CDK2-inhibitor. Accordingly, CCNE1and p16 are, together, a combination biomarker: cells that respond totreatment with a CDK2 inhibitor display an amplification of the CCNE1gene and/or an expression level of CCNE1 that is higher than a controlexpression level of CCNE1, and have a nucleotide sequence (e.g., a geneor an mRNA) that encodes the p16 protein (e.g., a p16 protein comprisingthe amino acid sequence of SEQ ID NO:1) and/or have p16 protein present,while control cells that do not respond to treatment with a CDK2inhibitor do not have an amplification of the CCNE1 gene and/or anexpression level of CCNE1 that is higher than a control expression levelof CCNE1, and tend to have a mutated or deleted gene that encodes thep16 protein and/or lack expression of p16 protein.

Thus, the disclosure provides a method of treating a human subjecthaving, suspected of having, or at risk of developing a disease ordisorder associated with CDK2, comprising administering to the humansubject a CDK2 inhibitor, wherein the human subject has been previouslydetermined to: (i) (a) have a nucleotide sequence encoding a p16 proteincomprising the amino acid sequence of SEQ ID NO:1, (b) have a CDKN2Agene lacking one or more inactivating nucleic acid substitutions and/ordeletions, and/or (c) express a p16 protein, and (ii) (a) have anamplification of the CCNE1 gene and/or (b) have an expression level ofCCNE1 in a biological sample obtained from the human subject that ishigher than a control expression level of CCNE1. In certain embodiments,the predictive methods described herein predict that the subject willrespond to treatment with the CDK2 inhibitor with at least 50%, at least60%, at least 70%, at least 80%, at least 90%, at least 95%, at least98% or 100% accuracy. For example, in some embodiments, if thepredictive methods described herein are applied to 10 subjects having,suspected of having, or at risk of developing a disease or disorderassociated with CDK2, and 8 of those 10 subjects are predicted torespond to treatment with a CDK2 inhibitor based on a predictive methoddescribed herein, and 7 of those 8 subjects do indeed respond totreatment with a CDK2 inhibitor, then the predictive method has anaccuracy of 87.5% (7 divided by 8). A subject is considered to respondto the CDK2 inhibitor if the subject shows any improvement in diseasestatus as evidenced by, e.g., reduction or alleviation in symptoms,disease remission/resolution, etc.

In some embodiments, the subject has a disease or disorder associatedwith CDK2. In some embodiments, the human subject has been previouslydetermined to: (i) (a) have a nucleotide sequence encoding a p16 proteincomprising the amino acid sequence of SEQ ID NO:1 and/or (b) a CDKN2Agene lacking one or more inactivating nucleic acid substitutions and/ordeletions, and (ii) have an amplification of the CCNE1 gene in abiological sample obtained from the human subject. In some embodiments,the CDKN2A gene encodes a protein comprising the amino acid sequence ofSEQ ID NO:1. In specific embodiments, the CDKN2A gene encodes a proteincomprising the amino acid sequence of SEQ ID NO:1.

In specific embodiments, the one or more inactivating nucleic acidsubstitutions and/or deletions in the CDKN2A gene is as described inTable 1. In specific embodiments, the one or more inactivating nucleicacid substitutions and/or deletions in the CDKN2A gene is as describedin Yarbrough et al., Journal of the National Cancer Institute,91(18):1569-1574, 1999; Liggett and Sidransky, Biology of Neoplasia,Journal of Oncology, 16(3):1197-1206, 1998, and Cairns et al., NatureGenetics, 11:210-212, 1995, each of which is incorporated by referenceherein in its entirety.

TABLE 1 CDKN2A gene substitutions, deletions, and modificationsDescription Reference(s) C to T transition converting RefSNP Accessioncodon 232 of the No. rs121913388; CDKN2A gene from an Kamb et al.,Science arginine codon to a stop 264: 436-440, codon 1994 19-basepairgermline deletion RefSNP Accession at nucleotide 225 No. rs587776716;causing a reading-frame shift Gruis et al., Nature predicted to severelyGenet. 10: 351-353, truncate p16 protein 1995 6-basepair deletion atClinVar Accession No. nucleotides 363-368 of the RCV000010017.2; CDKN2Agene Liu et al., Oncogene 11: 405-412, 1995 Mutation at chromosomeRefSNP Accession 9:21971058 predicted to No. rs104894094; substituteglycine corresponding Ciotti et al., Am. J. to amino acid Hum. Genet.67: position 101 of SEQ ID NO: 1 311-319, 2000 with a tryptophanGermline mutation constituting ClinVar Accession No. an in-frame3-basepair RCV000010020.3; duplication at nucleotide Borg et al., Cancer332 in exon 2 of Res. 56: 2497-2500, 1996 the CDKN2A gene Mutationpredicted to RefSNP Accession No. substitute methionine rs104894095;corresponding to amino acid Harland et al., Hum. position 53 of SEQ IDMolec. Genet. 6: NO: 1 with an isoleucine 2061-2067, 1997 Mutationpredicted to RefSNP Accession No. substitute arginine rs104894097;corresponding to amino acid Monzon etal., New Eng. position 24 of SEQ IDJ. Med. 338: NO: 1 with a proline 879-887, 1998 24-basepair repeatinserted RefSNP Accession at chromosome 9 No. rs587780668; between21974795 and 21974796 Pollock etal., Hum. (forward strand) Mutat. 11:424- 431, 1998) G-to-T transversion at ClinVar Accession No. nucleotide−34 of the RCV000010024.5; CDKN2A gene Liu et al., Nature Genet. 21:128-132, 1999 Deletion of the p14(ARF)-specific ClinVar Accession No.exon 1-beta of RCV000010026.2; CDKN2A Randerson-Moor et al., Hum. Molec.Genet. 10: 55-62, 2001 Mutation predicted to RefSNP Accession No.substitute valine rs104894098; corresponding to amino acid Goldsteinetal., Brit. J. position 126 of SEQ Cancer 85: 527- ID NO: 1 with anisoleucine 530, 2001 Transition (IVS2-105 A-G) ClinVar Accession No. inintron 2 of the RCV000010028.3; CDKN2A gene creating a Harland et al.,Hum. false GT splice donor site Molec. Genet. 10: 2679-2686, 105 bases5-prime of exon 3 2001 resulting in aberrant splicing of the mRNAMutation predicted to result RefSNP Accession in substitution of No.rs113798404; glycine corresponding to Hewitt et al., Hum. amino acidposition 122 of Molec. Genet. 11: SEQ ID NO: 1 with an arginine1273-1279, 2002 Mutation predicted to result RefSNP Accession insubstitution of valine No. rs113798404; corresponding to amino acidYakobson et al., position 59 of SEQ ID Melanoma Res. 11: NO: 1 with anarginine 569-570, 2001 Tandem germline339G-C RefSNP Accessiontransversion and a 340C- Nos. rs113798404 T transition in the CDKN2A andrs104894104; gene resulting in Kannengiesser etal., substitution ofproline Genes Chromosomes corresponding to amino acid Cancer 46: 751-position 114 of SEQ ID NO: 1 760, 2007 with a serine Mutation predictedto result in RefSNP Accession substitution of serine No. rs104894109;corresponding to amino acid Kannengiesser et al., Genes position 56 ofSEQ ID Chromosomes NO: 1 with an isoleucine Cancer 46: 751-760, 2007Mutation predicted to RefSNP Accession result in substitution of No.rs137854599; glycine corresponding to Goldstein et al., J. Med. aminoacid position 89 of Genet. 45: 284- SEQ ID NO: 1 with an 289, 2008aspartic acid Heterozygous A-to-G transition ClinVar Accession no. inexon 1B of the RCV000022943.3; CDKN2A gene, affecting Binni et al.,Clin. splicing of the p14(ARF) Genet. 77: 581-586, 2010 isoformHeterozygous 5-bp duplication ClinVar Accession No. (19_23dup) in theRCV000030680.6; CDKN2A gene, resulting Harinck, F., Kluijt et in aframeshift and al., J. Med. Genet. premature termination 49: 362-365,2012 Mutation predicted to result Yarbrough et al., Journal insubstitution of of the National Cancer aspartic acid correspondingInstitute, 91(18):1569- to amino acid position 1574 84 of SEQ ID NO: 1with a valine Mutation predicted to Yarbrough et al., result insubstitution of Journal of the aspartic acid corresponding NationalCancer to amino acid position Institute, 91(18):1569- 84 of SEQ ID NO: 1with a glycine 1574 Mutation predicted to result Yarbrough et al., insubstitution of Journal of the arginine corresponding to National Canceramino acid position 87 of Institute, 91(18):1569- SEQ ID NO: 1 with aproline 1574 Mutation predicted to result Yarbrough et al., insubstitution of Journal of the proline corresponding to National Canceramino acid position 48 of Institute, 91(18):1569- SEQ ID NO: 1 with aleucine 1574 Mutation predicted to result Yarbrough et al., insubstitution of Journal of the aspartic acid corresponding NationalCancer Institute, to amino acid position 74 of 91(18):1569- SEQ ID NO: 1with a asparagine 1574 Mutation predicted to Yarbrough et al., result insubstitution of Journal of the arginine corresponding to National Canceramino acid position 87 of Institute, 91(18):1569- SEQ ID NO: 1 with aleucine 1574 Mutation predicted to Yarbrough et al., result insubstitution of Journal of the asparagine corresponding National Cancerto amino acid position 71 Institute, 91(18):1569- of SEQ ID NO: 1 with aserine 1574 Mutation predicted to Yarbrough et al., result insubstitution of Journal of the arginine corresponding to National CancerInstitute, amino acid position 80 of 91(18):1569- SEQ ID NO: 1 with aleucine 1574 Mutation predicted to Yarbrough et al., result insubstitution of Journal of the histidine corresponding to NationalCancer Institute, amino acid position 83 of 91(18):1569- SEQ ID NO: 1with a tyrosine 1574

The disclosure also features a method of treating a human subjecthaving, suspected of having, or at risk of developing a disease ordisorder associated with CDK2, comprising: (i) identifying, inabiological sample obtained from the human subject: (a) a nucleotidesequence encoding ap16 protein comprising the amino acid sequence of SEQID NO: 1, (b) a CDKN2A gene lacking one or more inactivating nucleicacid substitutions, and/or (c) the presence of ap16 protein; (ii)identifying, in abiological sample obtained from the human subject: (a)an amplification of the CCNE1 gene and/or (b) an expression level ofCCNE1 that is higher than a control expression level of CCNE1; and (iii)administering a CDK2 inhibitor to the human subject. In someembodiments, the subject has a disease or disorder associated with CDK2.In some embodiments, the subject is suspected of having or is at risk ofdeveloping a disease or disorder associated with CDK2. In someembodiments, the method comprises: (i) identifying, in a biologicalsample obtained from the human subject: (a) a nucleotide sequenceencoding a p16 protein comprising the amino acid sequence of SEQ IDNO:1, (b) a CDKN2A gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions, and/or (c) the presence of a p16protein; (ii) identifying, in a biological sample obtained from thehuman subject: (a) an amplification of the CCNE1 gene; and (iii)administering a CDK2 inhibitor to the human subject.

The disclosure also features a method of predicting the response of ahuman subject having, suspected of having, or at risk of developing adisease or disorder associated with CDK2 to a CDK2 inhibitor,comprising: (i) determining, from a biological sample obtained from thehuman subject: (a) the nucleotide sequence of a CDKN2A gene, (b) thepresence of a CDKN2A gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions, and/or (c) the presence of a p16protein; and (ii) determining, from a biological sample obtained fromthe human subject: (a) the copy number of the CCNE1 gene and/or (b) theexpression level of CCNE1, wherein (1) (a) the presence of a CDKN2A geneencoding a p16 protein comprising the amino acid sequence of SEQ IDNO:1, (b) the presence of a CDKN2A gene lacking one or more inactivatingnucleic acid substitutions and/or deletions, and/or (c) the presence ofa p16 protein, and (2) (a) an amplification of the CCNE1 gene and/or (b)an expression level of CCNE1 that is higher than a control expressionlevel of CCNE1, is predictive that the human subject will respond to theCDK2 inhibitor. In some embodiments, the subject has a disease ordisorder associated with CDK2. In some embodiments, the subject issuspected of having or is at risk of developing a disease or disorderassociated with CDK2. In some embodiments, the method comprises: (i)determining, from a biological sample obtained from the human subject:(a) the nucleotide sequence of a CDKN2A gene and/or (b) the presence ofa CDKN2A gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions; and (ii) determining, from a biologicalsample obtained from the human subject: (a) the copy number of the CCNE1gene, wherein (1) (a) the presence of a CDKN2A gene encoding a p16protein comprising the amino acid sequence of SEQ ID NO:1 and/or (b) thepresence of a CDKN2A gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions, and (2) (a) an amplification of theCCNE1 gene, is predictive that the human subject will respond to theCDK2 inhibitor.

In specific embodiments, the (i) determining of (a) the nucleotidesequence of a CDKN2A gene, (b) the presence of a CDKN2A gene lacking oneor more inactivating nucleic acid substitutions and/or deletions, and/or(c) the presence of a p16 protein is performed before (e.g., at least 1day, at least 2 days, at least 3 days, at least 4 days, at least 5 days,at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, orat least 4 weeks, or from 6 hours to 16 hours, from 6 hours to 20 hours,or from 6 hours to 24 hours, from 2 days to 3 days, from 2 days to 4days, from 2 days to 5 days, from 2 days to 6 days, from 2 days to 7days, from 1 week to 2 weeks, from 1 week to 3 weeks, or from 1 week to4 weeks before) administering to the human subject the CDK2 inhibitor.In specific embodiments, the (ii) determining of (a) the copy number ofthe CCNE1 gene and/or (b) the expression level of CCNE1 in thebiological sample obtained from the human subject is performed before(e.g., at least 1 day, at least 2 days, at least 3 days, at least 4days, at least 5 days, at least 6 days, at least 7 days, at least 2weeks, at least 3 weeks, or at least 4 weeks, or from 6 hours to 16hours, from 6 hours to 20 hours, or from 6 hours to 24 hours, from 2days to 3 days, from 2 days to 4 days, from 2 days to 5 days, from 2days to 6 days, from 2 days to 7 days, from 1 week to 2 weeks, from 1week to 3 weeks, or from 1 week to 4 weeks before) administering to thehuman subject the CDK2 inhibitor.

An amplification of the CCNE1 gene and/or an expression level of CCNE1that is higher than a control expression level of CCNE1, combined withthe presence of a CDKN2A gene encoding a p16 protein comprising theamino acid sequence of SEQ ID NO:1, the presence of a CDKN2A genelacking one or more inactivating nucleic acid substitutions and/ordeletions, and/or the presence of a p16 protein (e.g., a p16 proteincomprising the amino acid sequence of SEQ ID NO:1), isindicative/predictive that a human subject having, suspected of having,or at risk of developing a disease or disorder associated with CDK2 willrespond to a CDK2 inhibitor.

In some embodiments, the CCNE1 gene is amplified to a gene copy numberfrom 3 to 25. In specific embodiments, the CCNE1 gene is amplified to agene copy number of at least 3. In specific embodiments, the CCNE1 geneis amplified to a gene copy number of at least 5. In specificembodiments, the CCNE1 gene is amplified to a gene copy number of atleast 7. In specific embodiments, the CCNE1 gene is amplified to a genecopy number of at least 10. In specific embodiments, the CCNE1 gene isamplified to a gene copy number of at least 12. In specific embodiments,the CCNE1 gene is amplified to a gene copy number of at least 14. Inspecific embodiments, the CCNE1 gene is amplified to a gene copy numberof at least 21.

In specific embodiments, the expression level of CCNE1 is the level ofCCNE1 mRNA. In specific embodiments, the expression level of CCNE1 isthe level of CCNE1 protein.

In some embodiments of the foregoing methods, the control expressionlevel of CCNE1 is a pre-established cut-off value. In some embodimentsof the foregoing methods, the control expression level of CCNE1 is theexpression level of CCNE1 in a sample or samples obtained from one ormore subjects that have not responded to treatment with the CDK2inhibitor.

In some embodiments of the foregoing methods, the expression level ofCCNE1 is the expression level of CCNE1 mRNA. In some embodiments of theforegoing methods, the expression level of CCNE1 is the expression levelof CCNE1 protein. In some embodiments in which the expression level ofCCNE1 is the expression level of CCNE1 mRNA, the expression level ofCCNE1 is measured by RNA sequencing, quantitative polymerase chainreaction (PCR), in situ hybridization, nucleic acid array or RNAsequencing. In some embodiments in which the expression level of CCNE1is the expression level of CCNE1 protein, the expression level of CCNE1is measured by western blot, enzyme-linked immunosorbent assay, orimmunohistochemistry staining.

Rb S780

The disclosure also features a method for assessing the CDKN2A gene andthe CCNE1 gene, comprising determining, from a biological sample orbiological samples obtained from a human subject having a disease ordisorder associated with CDK2, (i) (a) the nucleotide sequence of aCDKN2A gene or (b) the presence of a CDKN2A gene lacking one or moreinactivating nucleic acid substitutions and/or deletions, and (ii) thecopy number of the CCNE1 gene.

The disclosure also features a method of evaluating the response of ahuman subject having, suspected of having, or at risk of developing adisease or disorder associated with CDK2 to a CDK2 inhibitor,comprising: (a) administering a CDK2 inhibitor to the human subject,wherein the human subject has been previously determined to have anamplification of the CCNE1 gene and/or an expression level of CCNE1 thatis higher than a control expression level of CCNE1; (b) measuring, in abiological sample of obtained from the subject subsequent to theadministering of step (a), the level of retinoblastoma (Rb) proteinphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3, wherein a reduced level of Rb phosphorylation at theserine corresponding to amino acid position 780 of SEQ ID NO:3, ascompared to a control level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3, is indicativethat the human subject responds to the CDK2 inhibitor. In someembodiments, the subject has a disease or disorder associated with CDK2.In some embodiments, the subject is suspected of having or is at risk ofdeveloping a disease or disorder associated with CDK2. In someembodiments, the biological sample comprises a blood sample or a tumorbiopsy sample.

Phosphorylation of Rb at the serine corresponding to amino acid position780 of SEQ ID NO:3 (referred to herein as “Ser780” or “S780”) has beenidentified in the Examples as a pharmacodynamic marker useful inassessing responsiveness (e.g., inhibition by CDK2) of a human subjecthaving a disease or disorder having CCNE1 amplification to a CDK2inhibitor.

Rb is a regulator of the cell cycle and acts as a tumor suppressor. Rbis activated upon phosphorylation by cyclin D-CDK4/6 at Ser780 andSer795 and by cyclin E/CDK2 at Ser807 and Ser811. Rb is encoded by theRB transcriptional corepressor 1 (“RB1”) gene (GenBank Accession No.NM_000321). The amino acid sequence of human Rb is provided below(GenBank Accession No. NP_000312/UniProtKB Accession No. P06400) (S780is in bold and underlined):

(SEQ ID NO: 3)   1 MPPKTPRKTA ATAAAAAAEP PAPPPPPPPE    EDPEQDSGPE DLPLVRLEFE ETEEPDFTAL 61 CQKLKIPDHV RERAWLTWEK VSSVDGVLGG    YIQKKKELWG ICIFIAAVDL DEMSFTFTEL121 QKNIEISVHK FFNLLKEIDT STKVDNAMSR    LLKKYDVLFA LFSKLERTCE LIYLTQPSSS181 ISTEINSALV LKVSWITFLL AKGEVLQMED    DLVISFQLML CVLDYFIKLS PPMLLKEPYK241 TAVIPINGSP RTPRRGQNRS ARIAKQLEND    TRIIEVLCKE HECNIDEVKN VYFKNFIPFM301 NSLGLVTSNG LPEVENLSKR YEEIYLKNKD    LDARLFLDHD KTLQTDSIDS FETQRTPRKS361 NLDEEVNVIP PHTPVRTVMN TIQQLMMILN    SASDQPSENL ISYENNCTVN PKESILKRVK421 DIGYIFKEKF AKAVGQGCVE IGSQRYKLGV    RLYYRVMESM LKSEEERLSI QNFSKLLNDN481 IFHMSLLACA LEVVMATYSR STSQNLDSGT    DLSFPWILNV LNLKAFDFYK VIESFIKAEG541 NLTREMIKHL ERCEHRIMES LAWLSDSPLF    DLIKQSKDRE GPTDHLESAC PLNLPLQNNH601 TAADMYLSPV RSPKKKGSTT RVNSTANAET    QATSAFQTQK PLKSTSLSLF YKKVYRLAYL661 RLNTLCERLL SEHPELEHII WTLFQHTLQN    EYELMRDRHL DQIMMCSMYG ICKVKNIDLK721 FKIIVTAYKD LPHAVQETFK RVLIKEEEYD     SIIVFYNSVF MQRLKTNILQ YASTRPPTLS 781 PIPHIPRSPY KFPSSPLRIP GGNIYISPLK    SPYKISEGLP TPTKMTPRSR ILVSIGESFG841 TSEKFQKINQ MVCNSDRVLK RSAEGSNPPK    PLKKLRFDIE GSDEADGSKH LPGESKFQQK 901 LAEMTSTRTR MQKQKMNDSM DTSNKEEK.

As stated above, the Examples demonstrate CDK2-knockdown inhibitsproliferation in CCNE1-amplified cell lines, but not inCCNE-non-amplified cell lines. The Examples further demonstrateCDK2-knockdown or inhibition blocks Rb phosphorylation at the S780 inCCNE1-amplified cell lines, but not in CCNE1-non-amplified cell lines.Accordingly, Rb phosphorylation at the serine corresponding to aminoacid position 780 of SEQ ID NO:3 is a pharmacodynamic marker forassessing response to CDK2 inhibition in CCNE1 amplified cancer cells orpatients with diseases or disorders having CCNE1 amplification. Thus,provided herein are methods relating to the use of the level of Rbphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3 in a human subject having, suspected of having, or atrisk of developing a disease or disorder associated with CDK2 as amarker for indicating the response of the human subject to a CDK2inhibitor, wherein the human subject has an increased expression levelof CCNE1.

Thus, the disclosure features a method for measuring the amount of aprotein in a sample, comprising: (a) providing a biological sampleobtained from a human subject having a disease or disorder associatedwith CDK2; and (b) measuring the level of Rb protein phosphorylation atthe serine corresponding to amino acid position 780 of SEQ ID NO:3 inthe biological sample. In some embodiments, the biological samplecomprises a blood sample or a tumor biopsy sample. In a specificembodiment, provided herein is a method of evaluating the response of ahuman subject having, suspected of having, or at risk of developing adisease or disorder associated with CDK2 to a CDK2 inhibitor,comprising: (a) administering a CDK2 inhibitor to the human subject,wherein the human subject has been previously determined to have anamplification of the CCNE1 gene and/or an expression level of CCNE1 thatis higher than a control expression level of CCNE1; and (b) measuring,in a biological sample obtained from the human subject subsequent to theadministering of step (a), the level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3, wherein areduced level of Rb phosphorylation at the serine corresponding to aminoacid position 780 of SEQ ID NO:3, as compared to a control level of Rbphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3, is indicative that the human subject responds to theCDK2 inhibitor. In specific embodiments, the human subject has a diseaseor disorder associated with CDK2.

A reduced level of Rb phosphorylation at the serine corresponding toamino acid position 780 of SEQ ID NO:3, as compared to a control levelof Rb phosphorylation at the serine corresponding to amino acid position780 of SEQ ID NO:3, combined with an amplification of the CCNE1 geneand/or an expression level of CCNE1 that is higher than a controlexpression level of CCNE1, is indicative that a human subject having,suspected of having, or at risk of developing a disease or disorderassociated with CDK2 responds to a CDK2 inhibitor. For example, in asubject having an amplification of the CCNE1 gene and/or an expressionlevel of CCNE1 that is higher than a control expression level of CCNE1,a biological sample, obtained from the subject after treatment with aCDK2 inhibitor, having low (e.g., reduced as compared to a control) orundetectable levels of Rb phosphorylation at serine corresponding toamino acid position 780 of SEQ ID NO:3 is indicative that the subjectresponds to the CDK2 inhibitor.

A biological sample, obtained from a subject after administration of aCDK2 inhibitor to the subject, having a reduced level of Rbphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3, as compared to a control level of Rb phosphorylation atthe serine corresponding to amino acid position 780 of SEQ ID NO:3,combined with: (i) an amplification of the CCNE1 gene and/or anexpression level of CCNE1 that is higher than a control expression levelof CCNE1, and (ii) presence of a CDKN2A gene encoding a p16 proteincomprising the amino acid sequence of SEQ ID NO:1, presence of a CDKN2Agene lacking one or more inactivating nucleic acid substitutions and/ordeletions, and/or presence of a p16 protein (e.g., a p16 proteincomprising the amino acid sequence of SEQ ID NO:1), is indicative that ahuman subject having, suspected of having, or at risk of developing adisease or disorder associated with CDK2 responds to a CDK2 inhibitor.For example, in a human subject having (i) an amplification of the CCNE1gene and/or an expression level of CCNE1 that is higher than a controlexpression level of CCNE1, and (ii) the presence of a CDKN2A geneencoding a p16 protein comprising the amino acid sequence of SEQ IDNO:1, the presence of a CDKN2A gene lacking one or more inactivatingnucleic acid substitutions and/or deletions, and/or the presence of ap16 protein (e.g., a p16 protein comprising the amino acid sequence ofSEQ ID NO:1), a biological sample, obtained from the human subject afteradministration of a CDK2 inhibitor to the subject, having low (e.g.,reduced as compared to a control) or undetectable levels of Rbphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3 is indicative that the human subject responds to the CDK2inhibitor

In some embodiments, the CCNE1 gene is amplified to a gene copy numberfrom 3 to 25. In specific embodiments, the CCNE1 gene is amplified to agene copy number of at least 3. In specific embodiments, the CCNE1 geneis amplified to a gene copy number of at least 5. In specificembodiments, the CCNE1 gene is amplified to a gene copy number of atleast 7. In specific embodiments, the CCNE1 gene is amplified to a genecopy number of at least 10. In specific embodiments, the CCNE1 gene isamplified to a gene copy number of at least 12. In specific embodiments,the CCNE1 gene is amplified to a gene copy number of at least 14. Inspecific embodiments, the CCNE1 gene is amplified to a gene copy numberof at least 21. In specific embodiments, the expression level of CCNE1is the level of CCNE1 mRNA. In specific embodiments, the expressionlevel of CCNE1 is the level of CCNE1 protein.

Controls

As described above, the methods related to biomarkers andpharmacodynamic markers can involve, measuring one or more markers(e.g., a biomarker or a pharmacodynamics marker, e.g., the amplificationof the CCNE1 gene, the expression level of CCNE1, the presence of aCDKN2A gene encoding a p16 protein comprising the amino acid sequence ofSEQ ID NO:1, the presence of a CDKN2A gene lacking one or moreinactivating nucleic acid substitutions and/or deletions, the presenceof a p16 protein (e.g., a p16 protein comprising the amino acid sequenceof SEQ ID NO:1), and Rb phosphorylation at the serine corresponding toamino acid position 780 of SEQ ID NO:3) in a biological sample from ahuman subject having, suspected of having or at risk of developing adisease or disorder associated with CDK2. In specific embodiments, thehuman subject has a disease or disorder associated with CDK2. Inspecific embodiments, the human subject is suspected of having or is atrisk of developing a disease or disorder associated with CDK2. Incertain aspects, the level (e.g., amplification (e.g., for the CCNE1gene), expression level (e.g., for CCNE1 or p16 protein), orphosphorylation level (e.g., for Rb)) of one or more biomarkers,compared to a control level of the one or more biomarkers,predicts/indicates the response of a human subject to treatmentcomprising a CDK2 inhibitor. In certain embodiments, when (i) the CCNE1gene is amplified and/or an expression level of CCNE1 that is higherthan a control expression level of CCNE1, and (ii) a CDKN2A geneencoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1is present, a CDKN2A gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions is present, and/or a p16 protein (e.g., ap16 protein comprising the amino acid sequence of SEQ ID NO:1) ispresent, the human subject is identified as likely to respond to a CDK2inhibitor. In other embodiments, when (i) the CCNE1 gene is amplifiedand/or an expression level of CCNE1 that is higher than a controlexpression level of CCNE1, and (ii) in a biological sample from thehuman subject after the human subject has been administered a CDK2inhibitor, the level of Rb phosphorylation at the serine correspondingto amino acid position 780 of SEQ ID NO:3 is less than the control levelof Rb phosphorylation at the serine corresponding to amino acid position780 of SEQ ID NO:3, the human subject is identified as responding to aCDK2 inhibitor. In yet another embodiment, when (i) the CCNE1 gene isamplified and/or an expression level of CCNE1 that is higher than acontrol expression level of CCNE1, (ii) a CDKN2A gene encoding a p16protein comprising the amino acid sequence of SEQ ID NO:1 is present, aCDKN2A gene lacking one or more inactivating nucleic acid substitutionsand/or deletions is present, and/or a p16 protein (e.g., a p16 proteincomprising the amino acid sequence of SEQ ID NO:1) is present, and (iii)in a biological sample from the human subject after the human subjecthas been administered a CDK2 inhibitor, the level of Rb phosphorylationat the serine corresponding to amino acid position 780 of SEQ ID NO:3 isless than the control level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3, the humansubject is identified as responding to a CDK2 inhibitor. In thiscontext, the term “control” includes a sample (from the same tissuetype) obtained from a human subject who is known to not respond to aCDK2 inhibitor. The term “control” also includes a sample (from the sametissue type) obtained in the past from a human subject who is known tonot respond to a CDK2 inhibitor and used as a reference for futurecomparisons to test samples taken from human subjects for whichtherapeutic responsiveness is to be predicted. The “control” level(e.g., gene copy number, expression level, or phosphorylation level) fora particular biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in aparticular cell type or tissue may be pre-established by an analysis ofbiomarker level (e.g., expression level or phosphorylation level) in oneor more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 ormore) human subjects that have not responded to treatment with a CDK2inhibitor. This pre-established reference value (which may be an averageor median level (e.g., gene copy number, expression level, orphosphorylation level) taken from multiple human subjects that have notresponded to the therapy) may then be used for the “control” level ofthe biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in thecomparison with the test sample. In such a comparison, the human subjectis predicted to respond to a CDK2 inhibitor if the CCNE1 gene isamplified and/or the expression level of CCNE is higher than thepre-established reference, and a CDKN2A gene encoding a p16 proteincomprising the amino acid sequence of SEQ ID NO:1 is present, a CDKN2Agene lacking one or more inactivating nucleic acid substitutions and/ordeletions is present, and/or a p16 protein (e.g., a p16 proteincomprising the amino acid sequence of SEQ ID NO:1) is present. Inanother such a comparison, the human subject is predicted to respond toa CDK2 inhibitor if (i) CCNE1 gene is amplified and/or the expressionlevel of CCNE is higher than the pre-established reference, and (ii)after administering to the human subject a CDK2 inhibitor, the level ofRb phosphorylation at the serine corresponding to amino acid position780 of SEQ ID NO:3 is lower than the pre-established reference. In yetanother such a comparison, the human subject is indicated to respond toa CDK2 inhibitor if (i) CCNE1 gene is amplified and/or the expressionlevel of CCNE is higher than the pre-established reference, (ii) aCDKN2A gene encoding a p16 protein comprising the amino acid sequence ofSEQ ID NO:1 is present, a CDKN2A gene lacking one or more inactivatingnucleic acid substitutions and/or deletions is present, and/or a p16protein (e.g., a p16 protein comprising the amino acid sequence of SEQID NO:1) is present, and (iii) after administering to the human subjecta CDK2 inhibitor, the level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3 is lower thanthe pre-established reference.

The “control” level for a particular biomarker in a particular cell typeor tissue may alternatively be pre-established by an analysis ofbiomarker level in one or more human subjects that have responded totreatment with a CDK2 inhibitor. This pre-established reference value(which may be an average or median level (e.g., expression level orphosphorylation level) taken from multiple human subjects that haveresponded to the therapy) may then be used as the “control” level (e.g.,expression level or phosphorylation level) in the comparison with thetest sample. In such a comparison, the human subject is indicated torespond to a CDK2 inhibitor if the level (e.g., copy number of the CCNE1gene, expression level of CCNE1, expression level of p16, orphosphorylation level of Rb at the serine corresponding to amino acidposition 780 of SEQ ID NO:3) of the biomarker being analyzed is equal orcomparable to (e.g., at least 85% but less than 115% of), thepre-established reference.

In certain embodiments, the “control” is a pre-established cut-offvalue. A cut-off value is typically a level (e.g., a copy number, anexpression level, or a phosphorylation level) of a biomarker above orbelow which is considered predictive of responsiveness of a humansubject to a therapy of interest. Thus, in accordance with the methodsand compositions described herein, a reference level (e.g., of CCNE1gene copy number, CCNE1 expression, p16 expression, or Rbphosphorylation at the serine corresponding to amino acid position 780of SEQ ID NO:3) is identified as a cut-off value, above or below ofwhich is predictive of responsiveness to a CDK2 inhibitor. Cut-offvalues determined for use in the methods described herein can becompared with, e.g., published ranges of concentrations but can beindividualized to the methodology used and patient population.

In some embodiments, the expression level of CCNE1 is increased ascompared to the expression level of CCNE1 in a control. For example, theexpression level of CCNE1 analyzed can be at least 1.5, at least 2, atleast 3, at least 4, at least 5, at least 6, at least 7, at least 8, atleast 9, at least 10, at least 20, at least 25, at least 50, at least75, or at least 100 times higher, or at least 10%, at least 20%, atleast 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, at least 100%, at least 200%, at least 300%, atleast 400%, at least 500%, at least 600%, at least 700%, at least 800%,at least 900%, at least 1,000%, at least 1,500%, at least 2,000%, atleast 2,500%, at least 3,000%, at least 3,500%, at least 4,000%, atleast 4,500%, or at least 5,000% higher, than the expression level ofCCNE1 in a control.

A p16 protein is present if the protein is detectable by any assay knownin the art or described herein, such as, for example, western blot,immunohistochemistry, fluorescence-activated cell sorting, andenzyme-linked immunoassay. In some embodiments, a p16 protein is presentat an expression level that is within at least 5%, at least 10%, atleast 20%, or at least 30% of the p16 expression level in a healthycontrol.

In some embodiments, the level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3 being analyzedis reduced as compared to the level of Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3 in a control.For example, the level of the Rb phosphorylation at the serinecorresponding to amino acid position 780 of SEQ ID NO:3 being analyzedcan be at least 1.5, at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 20,at least 25, at least 50, at least 75, or at least 100 times lower, orat least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, or 100% lower, thanthe level of Rb phosphorylation at the serine corresponding to aminoacid position 780 of SEQ ID NO:3 in a control.

Biological Samples

Suitable biological samples for the methods described herein include anysample that contains blood or tumor cells obtained or derived from thehuman subject in need of treatment. For example, a biological sample cancontain tumor cells from biopsy from a patient suffering from a solidtumor. A tumor biopsy can be obtained by a variety of means known in theart. Alternatively, a blood sample can be obtained from a patientssuffering from a hematological cancer.

A biological sample can be obtained from a human subject having,suspected of having, or at risk of developing, a disease or disorderassociated with CDK2. In some embodiments, the disease or disorderassociated with CDK2 is a cancer (such as those described supra).

Methods for obtaining and/or storing samples that preserve the activityor integrity of molecules (e.g., nucleic acids or proteins) in thesample are well known to those skilled in the art. For example, abiological sample can be further contacted with one or more additionalagents such as buffers and/or inhibitors, including one or more ofnuclease, protease, and phosphatase inhibitors, which preserve orminimize changes in the molecules in the sample.

Evaluating Biomarkers and Pharmacodynamic Markers

Expression levels of CCNE1 or p16 can be detected as, e.g., RNAexpression of a target gene (i.e., the genes encoding CCNE1 or p16).That is, the expression level (amount) of CCNE1 or p16 can be determinedby detecting and/or measuring the level of mRNA expression of the geneencoding CCNE1. Alternatively, expression levels of CCNE1 or p16 can bedetected as, e.g., protein expression of target gene (i.e., the genesencoding CCNE1 or p16). That is, the expression level (amount) of CCNE1or p16 can be determined by detecting and/or measuring the level ofprotein expression of the genes encoding CCNE1 or p16.

In some embodiments, the expression level of CCNE1 or p16 is determinedby measuring RNA levels. A variety of suitable methods can be employedto detect and/or measure the level of mRNA expression of a gene. Forexample, mRNA expression can be determined using Northern blot or dotblot analysis, reverse transcriptase-PCR (RT-PCR; e.g., quantitativeRT-PCR), in situ hybridization (e.g., quantitative in situhybridization), nucleic acid array (e.g., oligonucleotide arrays or genechips) and RNA sequencing analysis. Details of such methods aredescribed below and in, e.g., Sambrook et al., Molecular Cloning: ALaboratory Manual Second Edition vol. 1, 2 and 3. Cold Spring HarborLaboratory Press: Cold Spring Harbor, N.Y., USA, November 1989; Gibsonet al. (1999) Genome Res., 6(10):995-1001; and Zhang et al. (2005)Environ. Sci. Technol., 39(8):2777-2785; U.S. Publication No.2004086915; European Patent No. 0543942; and U.S. Pat. No. 7,101,663;Kukurba et al. (2015) Cold Spring Harbor Protocols., 2015 (11): 951-69;the disclosures of each of which are incorporated herein by reference intheir entirety.

In one example, the presence or amount of one or more discrete mRNApopulations in a biological sample can be determined by isolating totalmRNA from the biological sample (see, e.g., Sambrook et al. (supra) andU.S. Pat. No. 6,812,341) and subjecting the isolated mRNA to agarose gelelectrophoresis to separate the mRNA by size. The size-separated mRNAsare then transferred (e.g., by diffusion) to a solid support such as anitrocellulose membrane. The presence or amount of one or more mRNApopulations in the biological sample can then be determined using one ormore detectably-labeled-polynucleotide probes, complementary to the mRNAsequence of interest, which bind to and thus render detectable theircorresponding mRNA populations. Detectable-labels include, e.g.,fluorescent (e.g., umbelliferone, fluorescein, fluoresceinisothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride, allophycocyanin, or phycoerythrin), luminescent (e.g.,europium, terbium, Qdot™ nanoparticles supplied by the Quantum DotCorporation, Palo Alto, Calif.), radiological (e.g., 125I, 131I, 35S,32P, 33P, or 3H), and enzymatic (horseradish peroxidase, alkalinephosphatase, beta-galactosidase, or acetylcholinesterase) labels.

In some embodiments, the expression level of CCNE1 or p16 is determinedby measuring protein levels. A variety of suitable methods can beemployed to detect and/or measure the level of protein expression oftarget genes. For example, CCNE1 or p16 protein expression can bedetermined using western blot, enzyme-linked immunosorbent assay(“ELISA”), fluorescence activated cell sorting, or immunohistochemistryanalysis (e.g., using a CCNE1-specific or p16-specific antibody,respectively). Details of such methods are described below and in, e.g.,Sambrook et al., supra.

In one example, the presence or amount of one or more discrete proteinpopulations (e.g., CCNE1 or p16) in a biological sample can bedetermined by western blot analysis, e.g., by isolating total proteinfrom the biological sample (see, e.g., Sambrook et al. (supra)) andsubjecting the isolated protein to agarose gel electrophoresis toseparate the protein by size. The size-separated proteins are thentransferred (e.g., by diffusion) to a solid support such as anitrocellulose membrane. The presence or amount of one or more proteinpopulations in the biological sample can then be determined using one ormore antibody probes, e.g., a first antibody specific for the protein ofinterest (e.g., CCNE1 or p16), and a second antibody, detectablylabeled, specific for the first antibody, which binds to and thusrenders detectable the corresponding protein population.Detectable-labels suitable for use in western blot analysis are known inthe art.

Methods for detecting or measuring gene expression (e.g., mRNA orprotein expression) can optionally be performed in formats that allowfor rapid preparation, processing, and analysis of multiple samples.This can be, for example, in multi-welled assay plates (e.g., 96 wellsor 386 wells) or arrays (e.g., nucleic acid chips or protein chips).Stock solutions for various reagents can be provided manually orrobotically, and subsequent sample preparation (e.g., RT-PCR, labeling,or cell fixation), pipetting, diluting, mixing, distribution, washing,incubating (e.g., hybridization), sample readout, data collection(optical data) and/or analysis (computer aided image analysis) can bedone robotically using commercially available analysis software,robotics, and detection instrumentation capable of detecting the signalgenerated from the assay. Examples of such detectors include, but arenot limited to, spectrophotometers, luminometers, fluorimeters, anddevices that measure radioisotope decay. Exemplary high-throughputcell-based assays (e.g., detecting the presence or level of a targetprotein in a cell) can utilize ArrayScan® VTI HCS Reader or KineticScan®HCS Reader technology (Cellomics Inc., Pittsburgh, Pa.).

In some embodiments, the presence of a CDKN2A gene encoding a p16protein comprising the amino acid sequence of SEQ ID NO:1 and/or thepresence of a CDKN2A gene lacking one or more inactivating nucleic acidsubstitutions and/or deletions is determined by evaluating the DNAsequence of the CDKN2A gene (e.g., genomic DNA or cDNA) or by evaluatingthe RNA sequence of the CDKN2A gene (e.g., RNA, e.g., mRNA). Methods ofperforming nucleic acid sequencing analyses are known in the art anddescribed above. Nonlimiting examples of inactivating nucleic acidsubstitutions and/or deletions preventing the CDKN2A gene from encodinga protein comprising the amino acid sequence of SEQ ID NO:1 aredescribed in Table 1, above. In specific embodiments, the one or moreinactivating nucleic acid substitutions and/or deletions in the CDKN2Agene is as described in Yarbrough et al., Journal of the National CancerInstitute, 91(18):1569-1574, 1999; Liggett and Sidransky, Biology ofNeoplasia, Journal of Oncology, 16(3):1197-1206, 1998, and Cairns etal., Nature Genetics, 11:210-212, 1995, each of which is incorporated byreference herein in its entirety.

In some embodiments, the expression level of a gene or the presence of agene lacking one or more inactivating nucleic acid substitutions ordeletions is determined by evaluating the copy number variation (CNV) ofthe gene. The CNV of genes (e.g., the CCNE1 gene and/or the CDKN2A gene)can be determined/identified by a variety of suitable methods. Forexample, CNV can be determined using fluorescent in situ hybridization(FISH), multiplex ligation dependent probe amplification (MLPA), arraycomparative genomic hybridization (aCGH), single-nucleotidepolymorphisms (SNP) array, and next-generation sequencing (NGS)technologies.

In one example, the copy number variation of one or more discrete genesin a biological sample can be determined by MLPA, e.g., by extractingDNA specimens from the biological sample (see, e.g., Sambrook et al.(supra) and U.S. Pat. No. 6,812,341), and amplifying DNA sequence ofinterest (e.g., CCNE1 or CDKN2A) using a mixture of MLPA probes. EachMLPA probe consists of two oligonucleotides that hybridize toimmediately adjacent target DNA sequence (e.g., CCNE1 or CDKN2A) inorder to be ligated into a single probe. Ligated probes are amplifiedthough PCR with one PCR primer fluorescently labeled, enabling theamplification products to be visualized during fragment separation bycapillary electrophoresis. The presence, absence or amplification of oneor more genes of interest in the biological sample is calculated bymeasuring PCR derived fluorescence, quantifying the amount of PCRproduct after normalization and comparing it with control DNA samples.

The level of Rb phosphorylation at the serine corresponding to aminoacid position 780 of SEQ ID NO:3 can be detected by a variety ofsuitable methods. For example, phosphorylation status can be determinedusing western blot, ELISA, fluorescence activated cell sorting, orimmunohistochemistry analysis. Details of such methods are describedbelow and in, e.g., Sambrook et al., supra.

As with the methods for detecting or measuring gene expression (above),methods for detecting or measuring the level of Rb phosphorylation atthe serine corresponding to amino acid position 780 of SEQ ID NO:3 canoptionally be performed in formats that allow for rapid preparation,processing, and analysis of multiple samples.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.,“Two-Pump at-Column Dilution Configuration for Preparative LC-MS,” K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification,” K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization,” K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument: Agilent 1100 series, LC/MSD; Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm; Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature (see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization,” K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge Cis 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature (See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization,” K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)). Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Intermediate 1.4-Chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a flask with a stir bar, a mixture of2,4-dichloro-5-(trifluoromethyl)pyrimidine (9.18 g, 42.3 mmol) intert-butanol (81 mL) and 1,2-dichloroethane (81 mL) was cooled to 0° C.in an ice bath before a 1 molar (M) solution of zinc chloride (60 mL, 60mmol) in diethyl ether was added and the resulting mixture was stirredat 0° C. for 1 hour. To the reaction mixture was then added1-(methylsulfonyl)piperidin-4-amine (7.18 g, 40.3 mmol), followed bydropwise addition of a solution of triethylamine (6.74 mL, 48.3 mmol) ina 1:1 mixture of 1,2-dichloroethane/tert-butanol (7 mL). The ice bathwas then removed and the reaction mixture was allowed to warm to r.t.before heating to 60° C. overnight. The reaction mixture was thenconcentrated to approximately 1/3 volume and diluted with water. Anoff-white precipitate formed and the mixture was slurried for 2 hours.The precipitate was then collected via filtration, washed with water,and dried under air. The crude product obtained was used directlywithout further purification. LCMS calculated for C₁₁H₁₅ClF₃N₄O₂S(M+H)⁺: m/z=359.1; Found: 359.0.

Intermediate 2.4-(1H-Imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a vial containing4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 1, 0.30 g, 0.836 mmol),tetrakis(triphenylphosphine)palladium (0) (0.048 g, 0.042 mmol), and4-(tributylstannyl)-1-trityl-1H-imidazole (0.501 g, 0.836 mmol) wasadded DMF (3.4 mL). The vial was flushed with nitrogen and a fresh capapplied, then the reaction heated to 100° C. for 18 hours.

After cooling to room temperature, the solution was filtered, washingwith MeOH (3.4 mL). Aqueous HCl (1 M aq, 3.4 mL) was added and thesolution heated to 80° C. for 1 hour. The reaction was cooled to roomtemperature and MeOH evaporated on rotovap. Additional aqueous HCl (1 M,3.4 mL) was added. The aqueous layer was extracted with EtOAc (3×) toremove unwanted organic byproducts. The aqueous layer was basified byaddition of NaOH to pH 13. This was extracted with DCM (5×). Thecombined organics were dried over sodium sulfate and evaporated todeliver the desired product which was used without further purification.LCMS calculated for C₁₄H₁₈F₃N₆O₂S (M+H)⁺: m/z=391.1; Found: 391.2.

Intermediate 3. tert-Butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (11.4 g, 52.5mmol) in tert-butanol (100 mL) and 1,2-dichloroethane (100 mL) wascooled to 0° C. in an ice bath before a 1 M solution of zinc chloride(75 mL, 75 mmol) in diethyl ether was added and the resulting mixturewas purged with nitrogen and stirred at 0° C. for 1 hour. To thereaction mixture was then added tert-butyl4-aminopiperidine-1-carboxylate (10.0 g, 49.9 mmol), followed bydropwise addition of a solution of triethylamine (8.35 mL, 59.9 mmol) ina 1:1 mixture of 1,2-dichloroethane/tert-butanol (15 mL). The ice bathwas then removed and the reaction mixture was allowed to warm to r.t.before heating to 60° C. overnight. After cooling to r.t., the reactionmixture was then concentrated to approximately 1/3 volume and dilutedwith water. Upon stirring an off-white precipitate formed and themixture was slurried for 1 hour. The precipitate was then collected viafiltration, washed with water and hexanes, and dried under air. Thecrude product obtained was used directly without further purification.LCMS calculated for C₁₁H₁₃ClF₃N₄O₂ (M-C₄H₈+H)⁺: m/z=325.1; Found 325.0.

Intermediate 4.4-Chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 3, 3.00 g, 7.88 mmol) in THF (39.4 mL) was purged withnitrogen and stirred at 80° C. for 10 minutes before a 4 M solution ofHCl in 1,4-dioxane (7.88 mL, 31.5 mmol) was added and the reactionmixture was stirred at 80° C. for 2 hours. After cooling to r.t., thereaction mixture was sparged with nitrogen for 5 minutes before1-methyl-1H-imidazole-4-sulfonyl chloride (1.71 g, 9.47 mmol) was addedfollowed by dropwise addition of triethylamine (6.59 mL, 47.3 mmol), andthe mixture was stirred at r.t. for 1 hour. The reaction mixture wasthen diluted with water and extracted with EtOAc and CH₂Cl₂. Thecombined organic phases were then dried over MgSO₄ and concentrated. Thecrude material obtained was used directly without further purification.LCMS calculated for C₁₄H₁₇ClF₃N₆O₂S (M+H)⁺: m/z=425.1; Found 425.1.

Intermediate 5.4-(1H-Imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:N,N-Dimethyl-4-(2-((1-((I-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamide

In a microwave vial with a stir bar, a mixture of4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 4, 250 mg, 0.588 mmol),N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide(177 mg, 0.588 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (96.0 mg, 0.118 mmol), sodiumcarbonate (187 mg, 1.77 mmol), acetonitrile (8 mL), and water (1.6 mL)was sparged with nitrogen and heated at 80° C. for 16 hours. Aftercooling to r.t., the solution was filtered through a pad of SiliaMetSThiol®, and concentrated. The residue was purified by flash columnchromatography (Agela Flash Column Silica-CS (24 g), eluting with agradient of 0 to 20% CH₂Cl₂/methanol) to affordN,N-dimethyl-4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamide,which was used in the next reaction without further purification. LCMScalculated for C₁₉H₂₅F₃N₉O₄S₂ (M+H)⁺: m/z=564.1; Found 564.2.

Step 2:4-(1H-Imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

TheN,N-dimethyl-4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamidefrom Step 1 was dissolved in EtOH (10 mL) and a 12 M aqueous solution ofHCl (1 mL). The solution was irradiated in a microwave reactor at 80° C.for 1 hour. After cooling to room temperature, the solution was washedwith Et₂O (10 mL). The resultant aqueous solution was then basified witha 1 M aqueous solution of NaOH. The solution was extracted with CH₂Cl₂(10 mL×3), and washed with brine (10 mL). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered, and concentrated to afford4-(1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(226 mg, 0.470 mmol, 80% yield over 2 steps). LCMS calculated forC₁₇H₂₀F₃N₈O₂S (M+H)⁺: m/z=457.1; Found 457.4.

Intermediate 6. tert-Butyl4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of 2,4-dichloropyrimidine-5-carbonitrile (23.89 g, 137 mmol)in tert-butanol (156 mL) and 1,2-dichloroethane (156 mL) was cooled to0° C. in an ice bath before a 1 M solution of zinc chloride (25.5 g, 187mmol) in diethyl ether was added and the resulting mixture was purgedwith nitrogen and stirred at 0° C. for 1 hour. To the reaction mixturewas then added tert-butyl 4-aminopiperidine-1-carboxylate (25 g, 125mmol), followed by slow addition of a solution of Hunig's base (32.7 mL,187 mmol) in a 1:1 mixture of 1,2-dichloroethane/tert-butanol (15 mL).The ice bath was then removed and the reaction mixture was allowed towarm to r.t. before heating to 60° C. overnight. After cooling to r.t.,the reaction mixture was then concentrated to approximately 1/3 volumeand poured into rapidly stirred water. Upon stirring, a precipitateformed and the mixture was slurried for 1 hour. The precipitate was thencollected via filtration, washed with water and hexanes, and dried underair. The crude product obtained was used directly without furtherpurification. LCMS calculated for C₁₁H₁₃ClN₅O₂ (M-C₄H₈+H)⁺: m/z=282.1;found 282.0.

Intermediate 7. tert-Butyl4-((4,5-dichloropyrimidin-2-yl)amino)piperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 6, using 2,4,5-trichloropyrimidine instead of2,4-dichloropyrimidine-5-carbonitrile as starting material. LCMScalculated for C₁₀H₁₃Cl₂N₄O₂ (M-C₄H₈+H)⁺: m/z=291.0; Found: 291.0.

Intermediate 8: N-(4-Chloro-3-methylpyridin-2-yl)acetamide

In a vial with a stir bar, a mixture of 4-chloro-3-methylpyridin-2-amine(62.5 mg, 0.438 mmol), acetic anhydride (0.50 mL, 5.3 mmol), andtriethylamine (1.0 mL, 7.2 mmol) was stirred at room temperature for 12hours. The resultant solution was concentrated. The crude productobtained was used directly without further purification. LCMS calculatedfor C₈H₁₀ClN₂O (M+H)⁺: m/z=185.0; Found 185.2.

Intermediate 9.4-Chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

This compound was prepared according to the procedures described inIntermediate 4, using tert-butyl4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 6) and methanesulfonyl chloride instead of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylateand 1-methyl-1H-imidazole-4-sulfonyl chloride as starting material. LCMScalculated for C₁₁H₁₅ClN₅O₂S (M+H)⁺: m/z=316.1; Found: 316.0.

Intermediate 10.4-(1H-Imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

This compound was prepared according to the procedures described inIntermediate 2, using4-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Intermediate 6) instead of4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₄H₁₈N₇O₂S (M+H)⁺: m/z=348.1;Found: 348.1.

Intermediate 11.4-Chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 4, using cyclopropanesulfonyl chloride instead of1-methyl-1H-imidazole-4-sulfonyl chloride as starting material. LCMScalculated for C₁₋₃H₁₇ClF₃N₄O₂S (M+H)⁺: m/z=385.1; Found: 385.1.

Intermediate 12.N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 2, using4-chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 11) instead of4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₆H₂₀F₃N₆O₂S (M+H)⁺:m/z=417.1; Found: 417.2.

Intermediate 13.4-(H-Imidazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 5, using tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 3) instead of4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material in Step 1. LCMS calculated for C₁₃H₁₆F₃N₆ (M+H)⁺:m/z=313.1; Found 313.2.

Intermediate 14. tert-Butyl4-((4-(H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a vial containing4-(1H-imidazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 13, 1.079 g, 3.46 mmol) and di-tert-butyl dicarbonate(0.795 mL, 3.46 mmol) was added DCM (34.6 mL). The mixture was stirredvigorously until full dissolution was achieved (about 10 minutes) thentriethylamine (1.441 mL, 10.37 mmol) was added dropwise at roomtemperature. The reaction was stirred for 30 minutes, at which point intime LCMS indicated completion. The crude reaction mixture wasconcentrated and purified by flash column chromatography (Agela FlashColumn Silica-CS (24 g), eluting with a gradient of 0 to 20%CH₂Cl₂/methanol) to afford tert-butyl4-((4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate,which was used in the next reaction without further purification. LCMScalculated for C₁₈H₂₄F₃N₆O₂ (M+H)⁺: m/z=413.2; Found 413.3.

Intermediate 15. tert-Butyl(3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 3, using tert-butyl(3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate instead of tert-butyl4-aminopiperidine-1-carboxylate as starting material. LCMS calculatedfor C₁₅H₂₀ClF₄N₄O₂ (M+H)⁺: m/z=399.1; Found 399.2.

Intermediate 16.4-Chloro-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 4, using tert-butyl(3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate(Intermediate 15) and methanesulfonyl chloride instead of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylateand 1-methyl-1H-imidazole-4-sulfonyl chloride as starting material. LCMScalculated for C₁₁H₁₄ClF₄N₄O₂S (M+H)⁺: m/z=377.1; Found 376.9.

Intermediate 17.N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 5, using4-chloro-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 16) instead of4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₄H₇F₄N₆O₂S (M+H)⁺:m/z=409.1; Found 409.2.

Intermediate 18.N-((3R,4S)-3-Fluoropiperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 5, using tert-butyl(3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate(Intermediate 15) instead of4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₃H₁₅F₄N₆ (M+H)⁺: m/z=331.1;Found 331.0.

Intermediate 19. tert-Butyl(3R,4S)-4-((4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 4, usingN-((3R,4S)-3-fluoropiperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 18) instead of4-(1H-imidazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₈H₂₃F₄N₆O₂ (M+H)⁺:m/z=431.2; Found 431.1.

Intermediate 20. tert-Butyl(3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 3, using tert-butyl(3R,4S)-4-amino-3-methylpiperidine-1-carboxylate instead of tert-butyl4-aminopiperidine-1-carboxylate as starting material. LCMS calculatedfor C₁₆H₂₃ClF₃N₄O₂ (M+H)⁺: m/z=395.2; Found 395.2.

Intermediate 21.4-Chloro-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 4, using tert-butyl(3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate(Intermediate 20) and methanesulfonyl chloride instead of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylateand 1-methyl-1H-imidazole-4-sulfonyl chloride as starting material. LCMScalculated for C₁₂H₁₇ClF₃N₄O₂S (M+H)⁺: m/z=373.1; Found 373.1.

Intermediate 22.4-(1H-Imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 5, using4-chloro-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 21) instead of4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₅H₂F₃N₆O₂S (M+H)⁺:m/z=405.1; Found 405.2.

Intermediate 23.4-(1H-Imidazol-4-yl)-N-((3R,4S)-3-methylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 5, using tert-butyl(3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate(Intermediate 20) instead of4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₄H₁₈F₃N₆ (M+H)⁺: m/z=327.2;Found 327.3.

Intermediate 24. tert-Butyl(3R,4S)-4-((4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 4, using4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 23) instead of4-(1H-imidazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₉H₂₆F₃N₆O₂ (M+H)⁺:m/z=427.2; Found 427.3.

Intermediate 25.6-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

To a vial containing 6-choro-3-fluoropicolinonitrile (0.38 g, 2.46 mmol)and cesium carbonate (2.00 g, 6.15 mmol) was added a solution of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2, 0.80 g, 2.05 mmol) in acetonitrile (30 mL). Thereaction was stirred at 80° C. for 2 hours. Upon cooling to roomtemperature the reaction was filtered and washed with acetonitrile. Thefiltrate was concentrated and then purified by flash columnchromatography (Agela Flash Column Silica-CS (24 g), eluting with agradient of 0 to 100% ethyl acetate/hexanes) to afford6-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile,which was used in the next reaction without further purification. LCMScalculated for C₂₀H₁₉ClF₃N₈O₂S (M+H)⁺: m/z=527.1; Found 527.2.

Intermediate 26.4-(1-(6-Chloro-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 25, using 6-chloro-3-fluoro-2-(trifluoromethyl)pyridineinstead of 6-chloro-3-fluoropicolinonitrile as the starting material.LCMS calculated for C₂₀H₁₉ClF₆N₇O₂S (M+H)⁺: m/z=570.1; Found 570.0.

Intermediate 27.4-(1-(6-Chloro-2-(difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 25, using 6-chloro-2-(difluoromethyl)-3-fluoropyridineinstead of 6-chloro-3-fluoropicolinonitrile as the starting material.LCMS calculated for C₂₀H₂ClF₅N₇O₂S (M+H)⁺: m/z=552.1; Found 552.0.

Intermediate 28.6-Methyl-5-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

Step 1: tert-Butyl4-((4-(1-(6-cyano-2-methylpyridin-3-yl)-H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

To a vial containing 5-fluoro-6-methylpicolinonitrile (0.051 g, 0.378mmol) and cesium carbonate (0.308 g, 0.946 mmol) was added a solution oftert-butyl4-((4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 14, 0.130 g, 0.315 mmol) in acetonitrile (3.94 mL). Thereaction was stirred at 80° C. for 1 hour, then the reaction was cooledto room temperature and filtered, washing with excess acetonitrile andDCM. The filtrate was concentrated and advanced to step 2 withoutfurther purification. LCMS calculated for C₂₅H₂₈F₃N₈O₂ (M+H)⁺:m/z=529.2; Found 529.3.

Step 2:6-Methyl-5-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-H-imidazol-1-yl)picolinonitrile

The crude tert-butyl4-((4-(1-(6-cyano-2-methylpyridin-3-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylatefrom step 1 was reconstituted in DCM (4 mL). Trifluoroacetic acid (0.483mlL, 6.30 mmol) was added and the reaction stirred at room temp for 1.5hours. LCMS indicated full conversion to desired product. The reactionwas concentrated on rotovap, dried on high vacuum and advanced to thenext step without further purification. LCMS calculated for C₂₀H₂₀F₃N₈(M+H)⁺: m/z=429.2; Found 429.2.

Intermediate 29.4-(1-(2-(Difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 28, using 2-(difluoromethyl)-3-fluoropyridine instead of5-fluoro-6-methylpicolinonitrile as the starting material for step 1.LCMS calculated for C₁₉H₁₉F₅N₇ (M+H)⁺: m/z=440.2; Found 440.0.

Intermediate 30.3-(4-(2-(Piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inIntermediate 28, using 3-fluoropicolinonitrile instead of5-fluoro-6-methylpicolinonitrile as the starting material for step 1.LCMS calculated for C₁₉H₁₈F₃N₈ (M+H)⁺: m/z=415.2; Found 415.1.

Intermediate 31.6-Methyl-3-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inIntermediate 28, using 3-fluoro-6-methylpicolinonitrile instead of5-fluoro-6-methylpicolinonitrile as the starting material for step 1.LCMS calculated for C₂₀H₂₀F₃N₈ (M+H)⁺: m/z=429.2; Found 429.2.

Intermediate 32.N-(Piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 28, using 3-fluoro-2-(trifluoromethyl)pyridine instead of5-fluoro-6-methylpicolinonitrile as the starting material for step 1.LCMS calculated for C₁₉H₁₈F₆N₇ (M+H)⁺: m/z=458.2; Found 458.0.

Intermediate 33.3-(4-(2-(Piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzonitrile

This compound was prepared according to the procedures described inIntermediate 28, using 3-fluoro-2-(trifluoromethyl)benzonitrile insteadof 5-fluoro-6-methylpicolinonitrile as the starting material for step 1.LCMS calculated for C₂₁H₁₈F₆N₇ (M+H)⁺: m/z=482.2; Found 482.0.

Intermediate 34.4-(1-(3-Bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 1, using 1-bromo-2-chloro-3-fluorobenzene instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₀H₂₀BrClF₃N₆O₂S (M+H)⁺: m/z=579.0; Found 579.1.

Intermediate 35.2-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde

Step 1:4-(1-(2-Chloro-3-vinylphenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a solution of4-(1-(3-bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 34, 0.411 g, 0.709 mmol), potassium carbonate (0.294 g,2.127 mmol), and XPhos Pd G3 (0.030 g, 0.035 mmol) in dioxane (2.95 mL)and water (0.591 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.364 mL, 2.127 mmol).The headspace was purged with nitrogen and heated to 50° C. for 18hours. Upon cooling to room temperature the reaction solution waspurified by flash column chromatography (Agela Flash Column Silica-CS(12 g), eluting with a gradient of 0 to 100% ethyl acetate/hexanes) toafford4-(1-(2-chloro-3-vinylphenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine,which was used in the next reaction without further purification. LCMScalculated for C₂₂H₂₃ClF₃N₆O₂S (M+H)⁺: m/z=527.1; Found 527.1.

Step 2:2-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde

To a solution of4-(1-(2-chloro-3-vinylphenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(0.192 g, 0.364 mmol) and sodium meta periodate (0.234 g, 1.093 mmol) inTHE (4.86 mL) and water (2.429 mL) was added an osmium tetroxide (0.223mL, 0.036 mmol) solution (4% in water). The reaction was stirredvigorously for 4 hours. LCMS indicated full conversion to desiredproduct. The reaction was quenched by addition of water and extractedinto DCM (3×). The combined organics were dried over sodium sulfate,concentrated on rotovap, and advanced to the next step without furtherpurification. LCMS calculated for C₂₁H₂₁ClF₃N₆O₃S (M+H)⁺: m/z=529.1;Found 529.1.

Intermediate 36.N-((3R,4R)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1: tert-Butyl(3R,4R)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 3, using tert-butyl(3R,4R)-4-amino-3-fluoropiperidine-1-carboxylate instead of tert-butyl4-aminopiperidine-1-carboxylate as starting material. LCMS calculatedfor C₁₁H₁₂ClF₄N₄O₂ (M+H-C₄H₈)⁺: m/z=343.1; Found: 343.0.

Step 2:4-Chloro-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 4, using tert-butyl(3R,4R)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylateand methanesulfonyl chloride instead of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 3) and 1-methyl-1H-imidazole-4-sulfonyl chloride asstarting material. LCMS calculated for C₁₁H₁₄ClF₄N₄O₂S (M+H)⁺:m/z=377.0; Found: 377.1.

Step 3:N-((3R,4R)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 5, using4-chloro-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineinstead of4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 4) as starting material. LCMS calculated for C₁₄H₁₇F₄N₆O₂S(M+H)⁺: m/z=409.1; Found: 409.2.

Intermediate 37.N,N,2-Trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide

Step 1: N,N,2-Trimethyl-1H-imidazole-1-sulfonamide

A mixture of 2-methyl-1H-imidazole (28.6 g, 348 mmol) and triethyl amine(48 mL, 350 mmol) was dissolved in DCM (1.6 L). Dimethylsulfamoylchloride (18.7 mL, 174 mmol) was added dropwise to the solution at 0° C.After stirring for 2 hours, the solution was stirred at room temperaturefor another 24 hours. The resultant mixture was concentrated underreduced pressure, and an off-white precipitate was formed. Theprecipitate was removed via filtration. The filtrate was distilled (0.5Torr, 110° C.) to give N,N,2-trimethyl-1H-imidazole-1-sulfonamide (20 g,106 mmol). LCMS calculated for C₆H₁₂N₃O₂S (M+H)⁺: m/z=190.1; Found:190.1.

Step 2:N,N,2-Trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide

In a 100 mL air free schlenk storage vessel with a stir bar, a mixtureof N,N,2-trimethyl-1H-imidazole-1-sulfonamide (3.61 g, 19.1 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (9.69 g,38.2 mmol), 4,4′-di-tert-butyl-2,2′-bipyridine (1.6 g, 6.0 mmol), and(1,5-cyclooctadiene)(methoxy)iridium(I) dimer (2.0 g, 3.0 mmol) indiethyl ether (25 mL) was purged with nitrogen. The mixture was shakenseveral times, and then stirred for 3 days in a water bath (23° C.). Theresultant solid mixture in the vessel was transferred into 1 L roundbottom flask by using hexanes (800 mL). After the slurry washed for 30minutes, the dark red color suspension was filtered, and washed withhexanes (100 mL). The residue was dissolved in EtOAc (400 mL). The darkred color solution was filtered through a pad of silica gel (100 g), andwashed with extra EtOAc (1600 mL). The solution was concentrated underreduced pressure. The obtained brown solid was attached to a vacuum lineover 24 hours to affordN,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide(3.0 g, 9.5 mmol). LCMS calculated for C₁₂H₂₃BN₃O₄S (M+H)⁺: m/z=316.1;Found: 316.1.

Intermediate 38.4-(2-Methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 5, usingN,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide(Intermediate 37) and4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 1) instead ofN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamideand4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 4) as starting material. LCMS calculated for C₁₅H₂₀F₃N₆O₂S(M+H)⁺: m/z=405.1; Found: 405.2.

Intermediate 39.N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 5, usingN,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide(Intermediate 37) and4-chloro-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 16) instead ofN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamideand4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 4) as starting material. LCMS calculated for C₁₅H₁₉F₄N₆O₂S(M+H)⁺: m/z=423.1; Found: 423.1.

Intermediate 40.4-(2-Methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

This compound was prepared according to the procedures described inIntermediate 5, usingN,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide(Intermediate 37) and4-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Intermediate 9) instead ofN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamideand4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 4) as starting material. LCMS calculated for C₁₅H₂₀N₇O₂S(M+H)⁺: m/z=362.1; Found: 362.1.

Intermediate 41.4-(1-(2-Fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:4-(1-(2-Fluoro-4-nitrophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, a mixture of 1,2-difluoro-4-nitrobenzene (203mg, 1.28 mmol),4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 38, 431 mg, 1.06 mmol), cesium carbonate (1041 mg, 3.20mmol), and acetonitrile (7.1 mL) was sparged with nitrogen. The mixturewas heated at 90° C. for 1 hour. After cooling to r.t., the resultantmixture was filtered and washed with acetonitrile. The filtrate wasconcentrated and the residue was used directly without furtherpurification. LCMS calculated for C₂₁H₂₂ClF₄N₇O₄S (M+H)⁺: m/z=544.1;Found 544.1.

Step 2:4-(1-(4-Amino-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of4-(1-(2-fluoro-4-nitrophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(1.42 g, 2.61 mmol) and iron (730 mg, 13.1 mmol) in water (2.90 mL) andEtOH (5.8 mL) was added ammonium chloride (14.0 mg, 0.26 mmol). Themixture was refluxed for 1 h. After cooling to room temperature, themixture was filtered through a pad of celite and washed by MeOH. Thefiltrate was concentrated and the residue was used directly withoutfurther purification. LCMS calculated for C₂₁H₂₄F₄N₇O₂S (M+H)⁺:m/z=514.2; Found 514.3.

Step 3:4-(1-(2-Fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To4-(1-(4-amino-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (from Step 2) wasadded HCl (1.0M aq. solution, 4.0 mL) and sodium nitrite (361 mg, 5.23mmol) at 0° C. After stirring for 5 min, potassium iodide (867 mg, 5.23mmol) was added and the mixture was stirred at room temperature for 30min. The reaction was quenched by sodium bicarbonate solution andNa₂S203 solution and extracted with DCM three times. The combinedorganic layers were dried over MgSO₄, filtered and concentrated. Theresidue was purified by column chromatography eluting with DCM/MeOH(0-10%) to give the titled compound. LCMS calculated for C₂₁H₂₂IF₄N₆O₂S(M+H)⁺: m/z=625.1; Found 625.1.

Intermediate 42.4-(1-(2-Chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, a mixture of 2-chloro-1-fluoro-4-iodobenzene(199 mg, 0.778 mmol),4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 2, 276 mg, 0.707 mmol), cesium carbonate(691 mg, 2.121 mmol), and N,N-dimethylacetamide (2.4 mL) was spargedwith nitrogen. The mixture was heated at 150° C. under microwaveirradiation for 80 minutes. After cooling to room temperature, theresultant mixture was filtered and the filtrate was diluted with DCM (20mL). The mixture was then washed with water five times. The organicphase was concentrated and purified by column chromatography on silicagel. LCMS calculated for C₂₀H₂₀ClF₃IN₆O₂S (M+H)⁺: m/z=627.0; Found627.0.

Intermediate 43.5-Chloro-4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine

Step 1:4,5-Dichloro-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 4, using tert-butyl4-((4,5-dichloropyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 7) and methanesulfonyl chloride instead of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(Intermediate 3) and 1-methyl-1H-imidazole-4-sulfonyl chloride asstarting material. LCMS calculated for C₁₀H₁₅Cl₂N₄O₂S (M+H)⁺: m/z=325.0;Found 325.0.

Step 2:5-Chloro-4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 5, using4,5-dichloro-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine(Step 1) instead of4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 4) as starting material. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆) δ 9.29 (s, 1H), 8.51 (s, 2H), 7.81-7.64 (m, 1H), 4.38-4.14 (m,1H), 3.64-3.49 (m, 2H), 3.00-2.80 (m, 5H), 2.03-1.88 (m, 2H), 1.69-1.47(m, 2H). LCMS calculated for C₁₃H₁₈ClN₆O₂S (M+H)⁺: m/z=357.1; Found357.1.

Example 1.3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

In a vial with a stir bar, a mixture of 3-chloro-4-fluorobenzonitrile(35.5 mg, 0.228 mmol),4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2, 50 mg, 0.128 mmol), cesium carbonate (94 mg, 0.289mmol), and acetonitrile (6 mL) was sparged with nitrogen. The mixturewas heated at 80° C. for 1 hour. After cooling to r.t., the resultantmixture was filtered and concentrated. The residue was purified by flashcolumn chromatography (Agela Flash Column Silica-CS (12 g), eluting witha gradient of 0 to 20% CH₂Cl₂/methanol). Fractions containing thedesired product were then concentrated, and the material obtained wasdissolved in acetonitrile and purified by prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min) to afford3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile.¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 343 K) δ 8.60 (s, 1H), 8.31 (d,J=1.6 Hz, 1H), 8.10 (s, 1H), 8.08 (brs, 1H), 8.02 (dd, J=8.2, 1.6 Hz,1H), 7.86 (d, J=8.2 Hz, 1H), 7.69 (m, 1H), 4.02 (m, 1H), 3.57 (m, 2H),2.92 (td, J=12.2, 2.7 Hz, 2H), 2.85 (s, 3H), 1.99 (m, 2H), 1.63 (m, 2H).LCMS calculated for C₂₁H₂₀ClF₃N₇O₂S (M+H)⁺: m/z=526.1; Found 526.1.

Example 2.3-Chloro-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 1, using 3-chloro-2-fluorobenzonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₁H₂₀ClF₃N₇O₂S (M+H)⁺: m/z=526.1; Found 526.1.

Example 3.4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde

This compound was prepared according to the procedures described inExample 1, using 3-chloro-4-fluorobenzaldehyde instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₁H₂₁ClF₃N₆O₃S (M+H)⁺: m/z=529.1; Found 529.1.

Step 2:4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, a mixture of3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehydefrom Step 1 (60 mg, 0.113 mmol), methanamine (170 μL, 0.340 mmol),acetic acid (60 μL, 1.05 mmol), and THE (3 mL) was stirred at roomtemperature for 12 hours. NaCNBH₃ (21.4 mg, 0.340 mmol) was then addedto the resultant mixture, followed by the addition of MeOH (3 mL). Afterthe solution was stirred for 12 hours, the mixture was concentrated. Thematerial obtained was dissolved in methanol and purified by prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). ¹H NMR (TFA salt, 500MHz, DMSO-d₆, 1:1 rotamers) δ 8.96 (brs, 2H), 8.65 (s, 0.5H), 8.59 (s,0.5H), 8.19 (s, 0.5H), 8.10 (d, J=1.0 Hz, 1H), 8.00 (s, 0.5H), 7.94-7.85(m, 2H), 7.81-7.72 (m, 1H), 7.65-7.59 (m, 1H), 4.24 (t, J=5.8 Hz, 2H),4.07-3.93 (m, 1H), 3.60-3.45 (m, 2H), 2.93-2.81 (m, 5H), 2.64-2.57 (m,3H), 2.00-1.91 (m, 2H), 1.64-1.53 (m, 2H). LCMS calculated forC₂₂H₂₆ClF₃N₇O₂S (M+H)⁺: m/z=544.2; Found 544.1.

Example 4.3-Chloro-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

In a microwave vial with a stir bar, a mixture of4-(1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 5, 10 mg, 0.022 mmol), 3-chloro-4-fluorobenzonitrile (10mg, 0.066 mmol), cesium carbonate (21 mg, 0.066 mmol), and DMSO (2 mL)was sparged with nitrogen and irradiated in the microwave at 100° C. for30 minutes. After cooling to r.t., the resultant mixture was dilutedwith acetonitrile, and filtered. The solution containing the desiredproduct was then purified by prep-LCMS (Sunfire C18 column, eluting witha gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to afford3-chloro-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile.LCMS calculated for C₂₄H₂₂ClF₃N₉₂O₂S (M+H)⁺: m/z=592.1; Found 592.3.

Example 5.3-Chloro-2-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 4, using 3-chloro-2-fluorobenzonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₄H₂₂ClF₃N₉O₂S (M+H)⁺: m/z=592.1; Found 592.3.

Example 6.4-(1-(2-Amino-5-fluoropyridin-4-yl)-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 4, using 4,5-difluoropyridin-2-amine instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₂H₂₃F₄N₁₀O₂S (M+H)⁺: m/z=567.2; Found 567.4.

Example 7.3-Methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inExample 4, using 4-chloro-3-methylpicolinonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₄H₂₄F₃N₁₀O₂S (M+H)⁺: m/z=573.2; Found 573.4.

Example 8.N-(3-Methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)pyridin-2-yl)acetamide

This compound was prepared according to the procedures described inExample 4, using N-(4-chloro-3-methylpyridin-2-yl)acetamide(Intermediate 8) instead of 3-chloro-4-fluorobenzonitrile as startingmaterial. LCMS calculated for C₂₅H₂₈F₃N₁₀O₃S (M+H)⁺: m/z=605.2; Found605.4.

Example 9.4-(1-(2-Amino-3-methylpyridin-4-yl)-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 4, using N-(4-chloro-3-methylpyridin-2-yl)acetamide(Intermediate 8) instead of 3-chloro-4-fluorobenzonitrile as startingmaterial. LCMS calculated for C₂₃H₂₆F₃N₁₀O₂S (M+H)⁺: m/z=563.2; Found563.4.

Example 10.4-(1-Methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a vial containing4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 4, 0.273 g, 0.643 mmol),1-methyl-4-(tributylstannyl)-1H-imidazole (0.276 g, 0.707 mmol), andtetrakis(triphenylphosphine)palladium (0) (0.037 g, 0.032 mmol) wasadded DMF (2.57 mL). The vial was flushed with nitrogen and a fresh capapplied, then the reaction heated to 100° C. for 18 hours. Based on LCMSthe starting material was fully consumed and converted to the desiredproduct. The reaction was cooled, diluted with ethyl acetate, andfiltered over celite, washing with additional ethyl acetate. Thefiltrate was concentrated then purified by flash column chromatography(Agela Flash Column Silica-CS (12 g), eluting with a gradient of 0 to20% CH₂Cl₂/methanol). LCMS calculated for C₁₈H₂₂F₃N₈O₂S (M+H)⁺:m/z=471.2; Found 471.2.

Example 11.4-(1-Methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 10, using4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 1) instead of4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₅H₂₀F₃N₆O₂S (M+H)⁺:m/z=405.1; Found 405.3.

Example 12.4-(2,5-Dichloro-1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a room temperature solution of4-(1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Example 11, 0.292 g, 0.722 mmol) in DCM (7.22 mL) was addedN-chlorosuccinimide (0.216 g, 1.588 mmol) in a single portion. Thereaction was warmed to 40° C. for 18 hours. After cooling to roomtemperature the reaction was quenched with sodium bicarbonate andextracted with DCM. The combined organics were dried over sodiumsulfate, filtered, and concentrated, then purified by flash columnchromatography (Agela Flash Column Silica-CS (12 g), eluting with agradient of 0 to 20% CH₂Cl₂/methanol). LCMS calculated forC₁₅H₁₈Cl₂F₃N₆O₂S (M+H)⁺: m/z=473.1; Found 473.1.

Example 13.4-(5-Bromo-1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a room temperature solution of4-(1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Example 11, 0.186 g, 0.460 mmol) in MeCN (4.60 mL) was addedN-bromosuccinimide (0.087 g, 0.483 mmol) in a single portion. Thereaction was stirred at room temperature for 2 hours then heated to 50°C. and stirred for an additional hour. The reaction was concentratedthen purified by flash column chromatography (Agela Flash ColumnSilica-CS (12 g), eluting with a gradient of 0 to 20% CH₂Cl₂/methanol).LCMS calculated for C₁₅H₁₉BrF₃N₆O₂S (M+H)⁺: m/z=483.0; Found 483.0.

Example 14.4-(5-Chloro-1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 13, using N-chlorosuccinimide instead of N-bromosuccinimide asstarting material. LCMS calculated for C₁₅H₁₉ClF₃N₆₀₂S (M+H)⁺:m/z=439.1; Found 439.2.

Example 15.4-(1,5-Dimethyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a vial containing4-(5-bromo-1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Example 13, 0.027 g, 0.056 mmol), tri-o-tolylphosphine (3.40 mg, 0.011mmol), and palladium(II) acetate (1.254 mg, 5.59 μmol) in DMF (0.559 mL)was added tetramethyltin (0.077 mL, 0.559 mmol). The reaction was heatedto 110° C. for 20 minutes. LCMS indicated full consumption of thestarting material and clean conversion to the desired product. Aftercooling to r.t., the resultant mixture was diluted with acetonitrile,and filtered. The solution containing the desired product was thenpurified by prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford4-(1,5-dimethyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.LCMS calculated for C₁₆H₂₂F₃N₆O₂S (M+H)⁺: m/z=419.2; Found 419.1.

Example 16.1-Methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-5-carbonitrile

To a vial containing4-(5-bromo-1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Example 13, 0.027 g, 0.056 mmol), zinc cyanide (0.033 g, 0.279 mmol),and tetrakis(triphenylphosphine)palladium (0) (0.016 g, 0.014 mmol) wasadded DMF (0.372 mL). The reaction was heated to 110° C. for 18 hours.LCMS indicated full consumption of the starting material and cleanconversion to the desired product. After cooling to r.t., the resultantmixture was diluted with acetonitrile and filtered. The solutioncontaining the desired product was then purified by prep-LCMS (SunfireC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to afford1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-5-carbonitrile.LCMS calculated for C₁₆H₁₉F₃N₇O₂S (M+H)⁺: m/z=430.1; Found 430.1.

Example 17.(1-Methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-2-yl)methanol

To a −78° C. solution of4-(1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Example 11, 0.031 g, 0.077 mmol) in THF (0.767 mL) was addedbutyllithium (0.184 mL, 0.460 mmol) dropwise. The resulting orangesolution was stirred at −78° C. for 30 minutes, then paraformaldehyde(2.302 mg, 0.077 mmol) was added. The reaction was stirred at −78° C.for 45 minutes then allowed to slowly warm to room temperature and stirovernight. The resultant mixture was diluted with acetonitrile andfiltered. The solution containing the desired product was then purifiedby prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford(1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-2-yl)methanol.LCMS calculated for C₁₆H₂₂F₃N₇O₃S (M+H)⁺: m/z=435.1; Found 435.1.

Example 18.2-Methyl-1-(1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-2-ol

This compound was prepared according to the procedures described inExample 17, using 2,2-dimethyloxirane instead of paraformaldehyde aselectrophile. LCMS calculated for C₁₉H₂₈F₃N₆O₃S (M+H)⁺: m/z=477.2; Found477.3.

Example 19.4-(1,2-Dimethyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 17, using iodomethane instead of paraformaldehyde aselectrophile. LCMS calculated for C₁₆H₂₂F₃N₆O₃S (M+H)⁺: m/z=419.2; Found419.2.

Example 20.4-(5-Chloro-1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 13, using N-chlorosuccinimide instead of N-bromosuccinimide andusing4-(1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Example 10) instead of4-(1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 343 K) δ 8.57(s, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.71 (d, J=6.2 Hz,1H), 3.88 (s, 1H), 3.74 (s, 3H), 3.66 (s, 3H), 3.63 (d, J=12.4 Hz, 1H),2.72 (td, J=12.0, 2.8 Hz, 2H), 1.97 (d, J=12.8 Hz, 2H), 1.62 (ddd,J=23.7, 11.0, 3.9 Hz, 2H). LCMS calculated for C₁₈H₂₁ClF₃N₈O₂S (M+H)⁺:m/z=505.1; Found 505.1.

Example 21.4-(1-(2,2-Difluoroethyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2, 10 mg, 0.026 mmol), 1,1-difluoro-2-iodoethane (9.8 mg,0.051 mmol) and cesium carbonate (25 mg, 0.077 mmol) in acetonitrile (1mL) was stirred at 80° C. for 3 h. After cooling to r.t., the resultantmixture was diluted with acetonitrile and filtered. The solutioncontaining the desired product was then purified by prep-LCMS (SunfireC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to afford4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.LCMS calculated for C₁₆H₂₀F₅N₆O₂S (M+H)⁺: m/z=455.1; Found 455.1.

Example 22.2-Methyl-1-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propan-2-ol

This compound was prepared according to the procedures described inExample 21, using 2,2-dimethyloxirane instead of1,1-difluoro-2-iodoethane as starting material. ¹H NMR (TFA salt, 500MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.12 (br, 1H), 7.99 (s, 1H), 7.87 (s, 1H),4.10 (s, 1H), 4.05 (br, 3H), 4.02 (s, 1H), 3.56 (d, J=11.8 Hz, 2H), 2.89(d, J=6.8 Hz, 3H), 1.97 (br, 2H), 1.61 (m, 2H), 1.10 (d, J=13.3 Hz, 6H).LCMS calculated for C₁₈H₂₆F₃N₆O₃S (M+H)⁺: m/z=463.2; Found 463.4.

Example 23.N-(1-(Methylsulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 21, using 2,2,2-trifluoroethyl 4-methylbenzenesulfonate insteadof 1,1-difluoro-2-iodoethane as starting material. LCMS calculated forC₁₆H₁₉F₆N₆O₂S (M+H)⁺: m/z=473.1; Found 473.0.

Example 24.N-(1-(Methylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 21, using tetrahydro-2H-pyran-4-yl methanesulfonate instead of1,1-difluoro-2-iodoethane as starting material. LCMS calculated forC₁₉H₂₆F₃N₆O₃S (M+H)⁺: m/z=475.2; Found 475.1.

Example 25.3-Cyclopropyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propanenitrile

This compound was prepared according to the procedures described inExample 21, using (E)-3-cyclopropylacrylonitrile and1,8-diazabicyclo[5.4.0]undec-7-ene instead of 1,1-difluoro-2-iodoethaneand cesium carbonate as starting material. LCMS calculated forC₂₀H₂₅F₃N₇O₂S (M+H)⁺: m/z=484.2; Found 484.1.

Example 26.4-(1-(2,2-Difluoroethyl)-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

This compound was prepared according to the procedures described inExample 21, using4-(1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Intermediate 10) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₆H₂₀F₂N₇O₂S (M+H)⁺:m/z=412.1; Found 412.1.

Example 27.4-(1-(2-Hydroxy-2-methylpropyl)-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

This compound was prepared according to the procedures described inExample 21, using4-(1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Intermediate 10) and 2,2-dimethyloxirane instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand 1,1-difluoro-2-iodoethane as starting material. LCMS calculated forC₁₈H₂₆N₇O₃S (M+H)⁺: m/z=420.2; Found 420.1.

Example 28.4-(1-(2-Chloro-4-cyanophenyl)-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

This compound was prepared according to the procedures described inExample 21, using4-(1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(Intermediate 10) and 3-chloro-4-fluorobenzonitrile instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand 1,1-difluoro-2-iodoethane as starting material. LCMS calculated forC₂₁H₂₀ClN₈O₂S (M+H)⁺: m/z=483.1; Found 483.1.

Example 29.N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 21, usingN-(1-(cyclopropylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 12) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₈H₂₂F₅N₆O₂S (M+H)⁺:m/z=481.1; Found 481.1. ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (d, 1H), 7.83(m, 2H), 7.69 (s, 1H), 4.79 (s, 1H), 3.99 (m, 1H), 3.95 (s, 2H), 3.62(d, J=12.3 Hz, 2H), 3.00 (d, J=10.5 Hz, 2H), 2.59 (m, 1H), 1.98 (m, 2H),1.62 (m, 2H), 1.08 (s, 6H), 1.00 (m, 2H), 0.95 (m, 2H).

Example 30.1-(4-(2-((1-(Cyclopropylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol

This compound was prepared according to the procedures described inExample 21, usingN-(1-(cyclopropylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 12) and 2,2-dimethyloxirane instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand 1,1-difluoro-2-iodoethane as starting material. LCMS calculated forC₂₀H₂₈F₃N₆O₃S (M+H)⁺: m/z=489.2; Found 489.2. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆) δ 8.64 (m, 1H), 8.45-7.76 (m, 6H), 7.72 (td, J=7.6, 1.2 Hz,1H), 4.06-3.99 (m, 2H), 3.54 (d, J=11.7 Hz, 2H), 2.97-2.82 (m, 5H), 1.99(t, J=13.0 Hz, 2H), 1.59 (dt, J=20.1, 9.7 Hz, 2H).

Example 31.2-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 4, using 2-fluorobenzonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₁H₂₁F₃N₇O₂S (M+H)⁺: m/z=492.1; Found 492.1. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆) δ 8.64 (m, 1H), 8.45-7.76 (m, 6H), 7.72 (td, J=7.6, 1.2 Hz,1H), 4.06-3.99 (m, 2H), 3.54 (d, J=11.7 Hz, 2H), 2.97-2.82 (m, 5H), 1.99(t, J=13.0 Hz, 2H), 1.59 (dt, J=20.1, 9.7 Hz, 2H).

Example 32.N-(1-(Methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 4, using 3-fluoro-2-(trifluoromethyl)pyridine instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₀H₂₀F₆N₇O₂S (M+H)⁺: m/z=536.1; Found 536.1. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆) δ 8.93 (d, J=4.7 Hz, 1H), 8.63 (m, 1H), 8.34-7.90 (m, 5H), 3.99(s, 1H), 3.54 (t, J=13.4 Hz, 2H), 2.94-2.79 (m, 5H), 2.03-1.89 (m, 2H),1.59 (t, J=11.6 Hz, 2H).

Example 33.6-Methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inExample 4, using 5-fluoro-6-methylpicolinonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₁H₂₂F₃N₈O₂S (M+H)⁺: m/z=507.2; Found 507.1. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆) δ 8.66 (d, J=30.4 Hz, 1H), 8.37-8.08 (m, 4H), 7.96 (t, J=6.5Hz, 1H), 4.03 (s, 1H), 3.55 (d, J=11.5 Hz, 2H), 2.90 (m, 5H), 2.52 (m,5H), 1.99 (d, J=12.7 Hz, 2H), 1.62 (t, J=10.7 Hz, 2H).

Example 34.3-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inExample 4, using 3-fluoropicolinonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₀H₂₀F₃N₈O₂S (M+H)⁺: m/z=493.1; Found 493.1. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆) δ 8.87 (d, J=4.7 Hz, 1H), 8.73-8.23 (m, 4H), 8.05-7.92 (m, 2H),4.02 (s, 1H), 3.55 (d, J=10.7 Hz, 2H), 2.89 (m, 5H), 2.01 (m, 2H), 1.60(p, J=10.9, 8.7 Hz, 2H).

Example 35.3-Methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 4, using 4-fluoro-3-methylbenzonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₂H₂₃F₃N₇O₂S (M+H)⁺: m/z=506.2; Found 506.2.

Example 36.6-Methyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inExample 1, using 3-fluoro-6-methylpicolinonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₁H₂₂F₃N₈O₂S (M+H)⁺: m/z=507.2; Found 507.1. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆) δ 8.65 (m, 1H), 8.47-8.16 (m, 3H), 7.97 (m, 1H), 7.84 (m, 1H),4.01 (s, 1H), 3.55 (d, J=11.6 Hz, 2H), 2.95-2.83 (m, 5H), 2.63 (s, 3H),1.99 (t, J=15.5 Hz, 2H), 1.67-1.53 (m, 2H).

Example 37.4-(1-(2-(Difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 1, using 3-fluoro-6-methylpicolinonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₀H₂₁F₅N₇O₂S (M+H)⁺: m/z=518.1; Found 518.2. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆) δ 8.86 (d, J=4.6 Hz, 1H), 8.64 (m, 1H), 8.28-7.99 (m, 3H), 7.94(d, J=7.7 Hz, 1H), 7.85 (td, J=8.3, 4.6 Hz, 1H), 6.95 (m, 1H), 4.00 (s,1H), 3.54 (t, J=13.6 Hz, 2H), 2.96-2.78 (m, 5H), 1.98 (m, 2H), 1.59 (t,J=12.5 Hz, 2H).

Example 38.3-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzonitrile

This compound was prepared according to the procedures described inExample 1, using 3-fluoro-6-methylpicolinonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₂H₂₀F₆N₇O₂S (M+H)⁺: m/z=560.1; Found 560.2. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆) δ 8.63 (m, 1H), 8.42-7.97 (m, 5H), 7.95 (t, J=8.5 Hz, 1H), 4.00(m, 1H), 3.60-3.47 (m, 2H), 2.87 (m, 5H), 1.96 (dq, J=12.2, 3.6 Hz, 2H),1.59 (h, J=11.6, 10.9 Hz, 2H).

Example 39.6-Methoxy-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

To a vial containing 6-chloro-3-fluoropicolinonitrile (0.038 g, 0.246mmol) and cesium carbonate (0.200 g, 0.615 mmol) was added a solution of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2, 0.08 g, 0.205 mmol) in acetonitrile (3 mL). Thereaction was stirred at 80° C. for 1 hour then cooled to roomtemperature and methanol (3 mL, 74.1 mmol) was added. The reaction washeated to 60° C. for 40 minutes at which point LCMS indicated reactioncompletion. Upon cooling to room temperature the reaction was diluted to10 mL with 1:1 acetonitrile:H₂O plus TFA (0.3 mL) and purified byprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford6-methoxy-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile.LCMS calculated for C₂₁H₂₂F₃N₈O₃S (M+H)⁺: m/z=523.2; Found 523.1. ¹H NMR(TFA salt, 500 MHz, DMSO-d₆) δ 8.64 (m, 1H), 8.44-8.12 (m, 3H), 7.97 (m,1H), 7.42 (dd, J=13.3, 8.9 Hz, 1H), 4.07-3.94 (m, 4H), 3.54 (m, 2H),2.94-2.83 (m, 5H), 2.05-1.92 (m, 2H), 1.68-1.53 (m, 2H).

Example 40.6-(2-(Dimethylamino)ethoxy)-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inExample 39 using 2-(dimethylamino)ethan-1-ol instead of methanol asstarting material. LCMS calculated for C₂₄H₂₉F₃N₉O₃S (M+H)⁺: m/z=580.2;Found 580.1. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆) δ 9.72 (s, 1H), 8.65(m, 1H), 8.43-8.13 (m, 3H), 7.96 (m, 1H), 7.44 (t, J=8.4 Hz, 1H),4.72-4.63 (m, 2H), 4.01 (s, 1H), 3.62-3.50 (m, 4H), 2.95-2.83 (m, 10H),2.00 (m, 2H), 1.60 (m, 2H).

Example 41.6-Ethyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

To a vial containing potassium carbonate (0.030 g, 0.216 mmol) and XPhosPd G3 (6.10 mg, 7.21 μmol) was added6-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile(Intermediate 25, 0.038 g, 0.072 mmol) in dioxane (0.401 mL).4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.026 mL, 0.144 mmol)was added followed by water (0.080 mL) and the solution heated to 50° C.for 40 minutes. LCMS indicated full consumption of starting material andconversion to the vinyl intermediate. The crude reaction was cooled toroom temperature and filtered through a pad of SiliaMetS Thiol®, rinsingwith MeOH (1 mL). To the filtrate was added palladium on carbon (onescoop) and the reaction was stirred under a hydrogen balloon for 2hours. LCMS indicated that hydrogenation was complete. The reaction wasfiltered over celite, diluted to 5 mL with 1:1 acetonitrile:H₂O andpurified by prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₂H₂₄F₃N₈O₂S (M+H)⁺: m/z=521.2; Found 521.2.

Example 42.3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylbenzonitrile

Step 1:2-Bromo-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

To a vial containing 2-bromo-3-fluorobenzonitrile (0.024 g, 0.122 mmol)and cesium carbonate (0.060 g, 0.184 mmol) was added a solution ofN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17, 0.025 g, 0.061 mmol) in acetonitrile (1 mL). Thereaction was stirred at 80° C. for 1.5 hours. Upon cooling to roomtemperature the reaction was filtered and washed with acetonitrile. Thefiltrate was concentrated and advanced to step 2 without furtherpurification. LCMS calculated for C₂₁H₁₉BrF₄N₇O₂S (M+H)⁺: m/z=588.0;Found 588.1.

Step 2:3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylbenzonitrile

To a vial containing crude2-bromo-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrilefrom step 1 was added tri-o-tolylphosphane (7.45 mg, 0.024 mmol),palladium(II) acetate (2.75 mg, 0.012 mmol), and tetramethylstannane(0.085 mL, 0.612 mmol) followed by DMF (0.8 mL). The reaction wasstirred at 110° C. for 6 hours. Upon cooling to room temperature thereaction filtered through a pad of SiliaMetS Thiol®, rinsing withacetonitrile (2 mL) then was diluted to 5 mL with 1:1 acetonitrile:H₂Oand purified by prep-LCMS (Sunfire C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LCMS calculated for C₂₂H₂₂F₄N₇O₂S (M+H)⁺: m/z=524.2; Found 524.3.

Example 43.2-Methyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 42, using4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2) instead ofN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material for step 1. LCMS calculated for C₂₂H₂₃F₃N₇O₂S(M+H)⁺: m/z=506.2; Found 506.2. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆) δ8.63 (m, 1H), 8.27-7.87 (m, 4H), 7.81 (dd, J=30.6, 8.0 Hz, 1H), 7.61 (q,J=7.6 Hz, 1H), 4.01 (dd, J=25.9, 9.9 Hz, 1H), 3.53 (m, 2H), 2.94-2.78(m, 5H), 2.35 (d, J=6.2 Hz, 3H), 1.96 (dt, J=12.2, 3.7 Hz, 2H), 1.60 (h,J=11.2, 10.0 Hz, 2H).

Example 44.4-(1-(6-Methyl-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a vial containing4-(1-(6-chloro-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 25, 0.265 g, 0.465 mmol), tri-o-tolylphosphine (0.028 g,0.093 mmol), and palladium(II) acetate (10.44 mg, 0.046 mmol) in DMF(4.65 mL) was added tetramethyltin (0.515 mL, 3.72 mmol). The headspacewas flushed with nitrogen, then the vial was capped and the reaction washeated to 110° C. for 40 minutes. Upon cooling to room temperature thereaction filtered through a pad of SiliaMetS Thiol®, rinsing withacetonitrile (5 mL) then was diluted to 20 mL with 1:1 acetonitrile:H₂Oand purified by prep-LCMS (Sunfire C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LCMS calculated for C₂₁H₂₂F₆N₇O₂S (M+H)⁺: m/z=550.2; Found 550.2. ¹H NMR(TFA salt, 500 MHz, DMSO-d₆) δ 8.63 (m, 1H), 8.21-7.89 (m, 4H), 7.83 (t,J=7.8 Hz, 1H), 3.99 (s, 1H), 3.58-3.48 (m, 2H), 2.87 (m, 5H), 2.66 (s,3H), 1.97 (d, J=12.6 Hz, 2H), 1.65-1.51 (m, 2H).

Example 45.2-Chloro-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 1, using 2-chloro-3-fluorobenzonitrile instead of3-chloro-4-fluorobenzonitrile andN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting materials. LCMS calculated for C₂₁H₁₉ClF₄N₇O₂S (M+H)⁺:m/z=544.1; Found 544.1. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 4:6rotamers) δ 8.66 (m, 1H), 8.38-7.96 (m, 5H), 7.78 (t, J=8.0 Hz, 1H),4.96 (m, 1H), 4.21 (m, 1H), 3.83 (s, 1H), 3.72-3.60 (m, 1H), 3.30-3.13(m, 1H), 3.00 (t, J=12.1 Hz, 1H), 2.91 (s, 3H), 1.96 (m, 1H), 1.84-1.74(m, 1H).

Example 46.N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(6-methyl-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 42, using 6-chloro-3-fluoro-2-(trifluoromethyl)pyridine insteadof 2-bromo-3-fluorobenzonitrile as starting material for step 1. LCMScalculated for C₂₁H₂₁F₇N₇O₂S (M+H)⁺: m/z=568.1; Found 568.1.

Example 47.3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inExample 1, using 3-fluoropicolinonitrile instead of3-chloro-4-fluorobenzonitrile andN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting materials. LCMS calculated for C₂₀H₁₉F₄N₈O₂S (M+H)⁺:m/z=511.1; Found 511.2. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆) δ 8.88 (m,1H), 8.73-8.28 (m, 4H), 8.10 (m, 1H), 8.00 (m, 1H), 4.99 (m, 1H),4.28-4.10 (m, 1H), 3.91-3.78 (m, 1H), 3.68 (d, J=13.3 Hz, 1H), 3.23 (m,1H), 3.09-2.95 (m, 1H), 2.92 (s, 3H), 1.98 (qt, J=12.2, 6.8 Hz, 1H),1.88-1.76 (m, 1H).

Example 48.N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 1, using 3-fluoro-2-(trifluoromethyl)pyridine instead of3-chloro-4-fluorobenzonitrile andN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting materials. LCMS calculated for C₂₀H₁₉F₇N₇O₂S (M+H)⁺:m/z=554.1; Found 554.1. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆) δ 8.94 (m,1H), 8.66 (m, 1H), 8.35-8.10 (m, 3H), 8.05 (m, 1H), 7.99 (m, 1H), 4.95(m, 1H), 4.19 (d, J=29.3 Hz, 1H), 3.83 (q, J=13.8 Hz, 1H), 3.71-3.60 (m,1H), 3.19 (m, 1H), 3.07-2.94 (m, 1H), 2.91 (m, 3H), 1.95 (dt, J=16.7,13.0 Hz, 1H), 1.85-1.73 (m, 1H).

Example 49.5-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile

This compound was prepared according to the procedures described inExample 1, using 5-fluoro-6-methylpicolinonitrile instead of3-chloro-4-fluorobenzonitrile andN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting materials. LCMS calculated for C₂₁H₂₁F₄N₈O₂S (M+H)⁺:m/z=525.1; Found 525.1. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆) δ 8.67 (d,J=13.7 Hz, 1H), 8.36 (s, 1H), 8.27-8.11 (m, 3H), 8.03 (m, 1H), 4.96 (m,1H), 4.29-4.11 (m, 1H), 3.82 (d, J=13.0 Hz, 1H), 3.66 (d, J=12.4 Hz,1H), 3.21 (m, 1H), 2.99 (t, J=11.4 Hz, 1H), 2.91 (s, 3H), 2.50 (s, 3H),1.96 (d, J=11.8 Hz, 1H), 1.80 (dd, J=13.7, 3.9 Hz, 1H).

Example 50.4-(1-(2-(Difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 1, using 2-(difluoromethyl)-3-fluoropyridine instead of3-chloro-4-fluorobenzonitrile andN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting materials. LCMS calculated for C₂₀H₂₀F₆N₇O₂S (M+H)⁺:m/z=536.1; Found 536.1. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆) δ 8.87 (m,1H), 8.66 (m, 1H), 8.34-7.97 (m, 3H), 7.86 (t, J=5.4 Hz, 1H), 6.96 (m,1H), 4.96 (m, 1H), 4.29-4.11 (m, 1H), 3.90-3.76 (m, 1H), 3.71-3.61 (m,1H), 3.20 (m, 1H), 3.09-2.94 (m, 1H), 2.91 (m, 3H), 2.03-1.91 (m, 1H),1.80 (dd, J=13.4, 4.0 Hz, 1H).

Example 51.3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile

This compound was prepared according to the procedures described inExample 1, using 3-fluoro-6-methylpicolinonitrile instead of3-chloro-4-fluorobenzonitrile andN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting materials. LCMS calculated for C₂₁H₂₁F₄N₈O₂S (M+H)⁺:m/z=525.2; Found 525.3.

Example 52.3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methoxypicolinonitrile

This compound was prepared according to the procedures described inExample 39, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₂₁H₂₁F₄N₈O₃S (M+H)⁺:m/z=541.1; Found 541.1.

Example 53.6-(2-(Dimethylamino)ethoxy)-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inExample 39, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand using 2-(dimethylamino)ethan-1-ol instead of methanol as startingmaterials. LCMS calculated for C₂₄H₂₈F₄N₉O₃S (M+H)⁺: m/z=598.2; Found598.2.

TABLE 2 The compounds in Table 2 were prepared in accordance with thesynthetic protocols set forth in Example 1 using the appropriatestarting materials. Ex. Name Structure Analytical data 544-(1-(2-Chloro-6- fluorophenyl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 519.1 55 4-(1-(2-Chlorophenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 501.2 56 2-Fluoro-6-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl) pyrimidin-4- yl)-1H-imidazol-1-yl)benzonitrile

LCMS found 510.1 57 4-Fluoro-2-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl) pyrimidin-4- yl)-1H-imidazol-1-yl)benzonitrile

LCMS found 510.1 58 2-Chloro-3-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl) pyrimidin-4- yl)-1H-imidazol-1-yl)benzonitrile

LCMS found 526.1 59 4-(4-(2-((1- (Methylsulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4- yl)-1H-imidazol-1-yl)isophthalonitrile

LCMS found 517.1 60 4-(1-(2,3- Dichlorophenyl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 535.1 61 2-Methyl-6-(4-(2-((1- (methylsulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4- yl)-1H-imidazol-1-yl)benzonitrile

LCMS found 506.1 62 2-Chloro-3-methyl-6- (4-(2-((1- (methylsulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-imidazol- 1-yl)benzonitrile

LCMS found 540.1 63 2-Bromo-3-(4-(2-((1- (methylsulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4- yl)-1H-imidazol-1-yl)benzonitrile

LCMS found 570.1 64 3-(4-(2-((1- (Methylsulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)- 1H-imidazol-1-yl)-6-(trifluoromethyl) picolinonitrile

LCMS found 561.2 65 4-(1-(2-Chloro-3- fluorophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 519.1 66 N-(1- (Methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(4- (trifluoromethyl)pyridin-3-yl)-1H-imidazol-4- yl)pyrimidin-2-amine

LCMS found 536.1 67 3-(4-(2-((1- (Methylsulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4- yl)-1H-imidazol-1-yl)isonicotinonitrile

LCMS found 493.1 68 2-(4-(2-(((3R,4S)-3- Fluoro-1- (methylsulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-imidazol- 1-yl)-5- (trifluoromethyl) benzonitrile

LCMS found 578.2 69 3-(4-(2-(((3R,4S)-3- Fluoro-1- (methylsulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-imidazol- 1-yl)-2- (trifluoromethyl) benzonitrile

LCMS found 578.2

TABLE 3 The compounds in Table 3 were prepared in accordance with thesynthetic protocols set forth in Example 39 using the appropriatestarting materials. Ex. Name Structure Analytical data 704-(1-(6-Methoxy-2- (trifluoromethyl) pyridin-3-yl)- 1H-imidazol-4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 566.2 71 2-Methyl-4-((5-(4-(2- ((1-(methylsulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-imidazol- 1-yl)-6- (trifluoromethyl) pyridin-2-yl)oxy)butan-2-ol

LCMS found 638.3 72 4-(1-(6-(2- (Dimethylamino) ethoxy)-2-(trifluoromethyl) pyridin-3- yl)-1H-imidazol-4- yl)-N-(1-(methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 623.3 73 4-(1-(6-((1- (Dimethylamino) propan-2- yl)oxy)-2-(trifluoromethyl) pyridin-3-yl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 637.3 74 2-((5-(4-(2-((1- (Methylsulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4- yl)-1H-imidazol- 1-yl)-6-(trifluoromethyl) pyridin-2- yl)oxy)propanenitrile

LCMS found 605.3 75 4-(1-(2- (Difluoromethyl)-6- methoxypyridin-3-yl)-1H-imidazol-4-yl)-N- (1-(methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 548.1 76 6-(2- (Ethyl(methyl)amino) ethoxy)-3-(4-(2-((1-(methylsulfonyl) piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-1H-imidazol- 1-yl)picolinonitrile

LCMS found 594.3

Example 77.4-(1-(2-Chloro-3-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a room temperature solution of2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde(Intermediate 35, 0.020 g, 0.038 mmol) and dimethylamine (0.023 mL,0.045 mmol) in DCE (0.5 mL) was added sodium triacetoxyborohydride(0.012 g, 0.057 mmol) in a single portion. The reaction was stirred atroom temperature for 1 hour at which point LCMS indicated fullconsumption of the aldehyde and conversion to desired product. Thereaction was diluted to 5 mL with 1:1 acetonitrile:MeOH and purified byprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₃H₂₈ClF₃N₇O₂S (M+H)⁺: m/z=558.2; Found 558.1.

TABLE 4 The compounds in Table 4 were prepared in accordance with thesynthetic protocols set forth in Example 77 using the appropriate aminestarting material. Ex. Name Structure Analytical data 784-(1-(2-Chloro-3-((4- methylpiperazin-1- yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 613.2 79 4-(1-(2-Chloro-3-(((4- methyltetrahydro-2H-pyran-4-yl) amino)methyl)phenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 628.3 80 4-(1-(2-Chloro-3- ((methylamino)methyl)phenyl)-1H-imidazol- 4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 544.2 81 4-(1-(2-Chloro-3- ((cyclopropylamino)methyl)phenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 570.2 82 1-(2-Chloro-3-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-ol

LCMS found 586.2

Example 83.1-(2-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethan-1-ol

To a solution of2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde(Intermediate 35, 0.015 g, 0.028 mmol) in THF (0.5 mL) was addedmethylmagnesium bromide (0.047 mL, 0.142 mmol). The reaction was stirredfor 10 minutes at room temperature at which point LCMS indicated fullconsumption of starting material and conversion to the desired product.The reaction was quenched with H₂O (0.5 mL) and diluted to 5 mL with 1:1acetonitrile:MeOH then purified by prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₂H₂₅ClF₃N₆O₃S (M+H)⁺:m/z=545.1; Found 545.1.

TABLE 5 The compounds in Table 5 were prepared in accordance with thesynthetic protocols set forth in Example 83 using the appropriatereductant. Ex. Name Structure Analytical data 84 (2-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol- 1-yl)phenyl)methanol

LCMS found 531.1 85 1-(2-Chloro-3-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)phenyl)propan-1-ol

LCMS found 559.1 86 (2-chloro-3-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)phenyl)(cyclopropyl) methanol

LCMS found 571.1

Example 87.3-(4-(2-((1-(Ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile

To a solution of6-methyl-3-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile(Intermediate 31, 0.019 g, 0.045 mmol) in THF (0.450 mL) was addedethanesulfonyl chloride (6.4 μL, 0.068 mmol) followed by dropwiseaddition of triethylamine (0.063 mL, 0.450 mmol). The reaction wasstirred at room temperature for 1 hour at which point LCMS showed fullconversion to the desired product. The reaction was diluted to 5 mL with1:1 acetonitrile:H₂O then purified by prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₂H₂₄F₃N₈O₂S (M+H)⁺:m/z=521.2; Found 521.1.

TABLE 6 The compounds in Table 6 were prepared in accordance with thesynthetic protocols set forth in Example 87 using the appropriatestarting materials. Ex. Name Structure Analytical data 88 4-(1-(2-(Difluoromethyl)pyridin- 3-yl)-1H-imidazol-4- yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl) piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 584.2 89 3-(4-(2-((1- (Ethylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)picolinonitrile

LCMS found 507.1 90 3-(4-(2-((1-((1,5- Dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H- imidazol-1-yl)-6- methylpicolinonitrile

LCMS found 587.3 91 N-(1- (Cyclopropylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(2- (trifluoromethyl)pyridin-3-yl)-1H-imidazol-4- yl)pyrimidin-2-amine

LCMS found 562.2 92 3-(4-(2-((1- (Cyclopropylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)- 2-(trifluoromethyl) benzonitrile

LCMS found 586.3 93 5-(4-(2-((1- (Ethylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile

LCMS found 521.1

TABLE 7 The compounds in Table 7 were prepared in accordance with thesynthetic protocols set forth in Example 41 using the appropriatestarting materials. Ex. Name Structure Analytical data 94 3-(4-(2-((1-(Methylsulfonyl) piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H- imidazol-1-yl)-6- propylpicolinonitrile

LCMS found 535.3 95 4-(1-(6-Ethyl-2- (trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)- N-(1-(methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 564.2

Example 96.4-(1-(3-(2-Aminopyridin-4-yl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a vial containing4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.019 g,0.086 mmol), potassium carbonate (0.018 g, 0.129 mmol), and XPhos Pd G3(3.65 mg, 4.31 μmol) was added a solution of4-(1-(3-bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 34, 0.025 g, 0.043 mmol) in dioxane (0.180 mL) followed bywater (0.036 mL). The headspace was purged with nitrogen then the vialcapped and heated to 80° C. for 2 hours. The crude reaction was cooledto room temperature and filtered through a pad of SiliaMetS Thiol®,rinsing with MeOH (1 mL). The solution was then diluted to 5 mL with 1:1acetonitrile:H₂O and purified by prep-LCMS (Sunfire C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). LCMS calculated for C₂₅H₂₅ClF₃N₈O₂S (M+H)⁺: m/z=593.2;Found 593.0.

TABLE 8 The compounds in Table 8 were prepared in accordance with thesynthetic protocols set forth in Example 96 using the appropriatestarting materials. Ex. Name Structure Analytical data 974-(1-(2-chloro-3- (Pyridin-3-yl)phenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 578.2 98 4-(1-(6-(1-Methyl-1H- pyrazol-4-yl)-2-(trifluoromethyl)pyridin- 3-yl)-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 616.2

Example 99.5-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-(trifluoromethyl)picolinonitrile

To a vial containing4-(1-(6-chloro-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 26, 0.044 g, 0.077 mmol), zinc cyanide (0.027 g, 0.231mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.013 g, 0.015 mmol) was added DMF (0.5 mL). Thevial was purged with nitrogen then heated to 110° C. for 16 hours. Thecrude reaction was cooled to room temperature and filtered through a padof SiliaMetS Thiol®, rinsing with MeOH (1 mL). The solution was thendiluted to 5 mL with 1:1 acetonitrile:H₂O and purified by prep-LCMS(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₁H₉F₆N₈O₂S (M+H)⁺: m/z=561.1; Found 561.2.

TABLE 9 The compounds in Table 9 were prepared in accordance with thesynthetic protocols set forth in Example 99 using the appropriatestarting materials. Analytical Ex. Name Structure data 1006-(Difluoromethyl)- 5-(4-(2-((1-(methyl- sulfonyl)piperidin-4-yl)amino)-5-(trifluoro- methyl)pyrimidin-4- yl)-1H-imidazol-1-yl)picolinonitrile

LCMS found 543.2

Example 101.4-(1-(4-(4-(Dimethylamino)piperidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 41, 25 mg, 0.040 mmol) and N,N-dimethylpiperidin-4-amine(15.4 mg, 0.120 mmol) in toluene (0.27 mL) and dioxane (0.13 mL) wasadded tris(dibenzylideneacetone)dipalladium (0):BINAP:sodiumtert-butoxide (0.05:0.15:2 molar ratio) (13.3 mg). The mixture wasdegassed with N₂ and then stirred in a sealed vial at 100° C. for 1 h.After cooling to room temperature, the reaction mixture wasconcentrated. The residue was then diluted with MeOH, filtered and thefiltrate was purified by prep HPLC (Sunfire C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1 rotamers) δ 9.51 (s,1H), 8.61 (s, 0.5H), 8.55 (s, 0.5H), 7.89 (s, 0.5H), 7.86 (d, J=7.6 Hz,1H), 7.68 (s, 0.5H), 7.43 (t, J=8.9 Hz, 1H), 7.13-7.04 (m, 1H), 6.93 (d,J=7.5 Hz, 1H), 4.07-3.98 (m, 2H), 3.95 (m, 1H), 3.52 (m, 2H), 3.36 (m,1H), 2.90-2.81 (m, 7H), 2.78 (s, 3H), 2.77 (s, 3H), 2.20 (s, 3H), 2.06(m, 2H), 1.95 (m, 2H), 1.63 (m, 2H), 1.57 (m, 2H). LCMS calculated forC₂₈H₃₇F₄N₈O₂S (M+H)⁺: m/z=625.3; Found 625.4.

Example 102.4-(1-(2-Fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound is a major side-product from deiodination of4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 41) under the C—N coupling reaction condition (the sameprocedure described in Example 101). This compound was purified by prepHPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₁H₂₃F₄N₆O₂S (M+H)⁺: m/z=499.2; Found 499.2.

Example 103.4-(1-(2-Fluoro-4-(4-methylpiperazin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 101, using 1-methylpiperazine instead ofN,N-dimethylpiperidin-4-amine as starting material. ¹H NMR (TFA salt,400 MHz, DMSO-d₆, 4:6 rotamers) δ 10.31 (s, 1H), 8.65 (s, 0.4H), 8.60(s, 0.6H), 8.02 (m, 1H), 7.98 (s, 0.6H), 7.82 (s, 4H), 7.63-7.45 (m,1H), 7.16 (d, J=7.4 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 4.01 (m, 3H), 3.53(m, 6H), 3.13 (m, 4H), 2.89 (m, 6H), 2.30 (d, J=8.0 Hz, 3H), 1.95 (m,2H), 1.58 (n, 2H). LCMS calculated for C₂₆H₃₃F₄N₈O₂S (M+H)⁺: m/z=597.2;Found 597.2.

TABLE 10 The compounds in Table 10 were prepared in accordance with thesynthetic protocols set forth in Example 101 using the appropriatestarting materials. Analytical Ex. Name Structure data 1044-(1-(2-Fluoro-4- (7-methyl-2,7- diazaspiro[3.5]- nonan-2-yl)phenyl)-2-methyl-1H- imidazol-4-yl)-N- (1-(methylsulfonyl)- piperidin-4-yl)-5-(trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 637.3 105 4-(1-(2-Fluoro-4- (4-isopropyl-piperazin-1-yl)- phenyl)-2-methyl- 1H-imidazol-4-yl)- N-(1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 625.3 106 (S)-4-(1-(4-(3- (Dimethylamino)-piperidin-1-yl)- 2-fluorophenyl)- 2-methyl-1H- imidazol-4-yl)-N-(1-(methyl- sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin-2-amine

LCMS [M + H]: found 625.3 107 4-(1-(2-Fluoro-4- (4-(methylamino)-piperidin-1-yl)- phenyl)-2-methyl- 1H-imidazol-4-yl)- N-(1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 611.2 108 4-(3-Fluoro-4-(2- methyl-4-(2-((1-(methylsulfonyl)- piperidin-4-yl)- amino)-5-(trifluoro-methyl)pyrimidin- 4-yl)-1H-imidazol- 1-yl)phenyl)-1- methylpiperazin-2-one

LCMS [M + H]: found 611.2 109 (R)-4-(1-(4-(3- (Dimethylamino)-pyrrolidin-1-yl)- 2-fluorophenyl)- 2-methyl-1H- imidazol-4-yl)-N-(1-(methyl- sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin-2-amine

LCMS [M + H]: found 611.2 110 (S)-4-(1-(4-(3- (Dimethylamino)-pyrrolidin-1-yl)- 2-fluorophenyl)- 2-methyl-1H- imidazol-4-yl)-N-(1-(methyl- sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin-2-amine

LCMS [M + H]: found 611.2 111 4-(1-(2-Fluoro-4- (piperazin-1-yl)-phenyl)-2-methyl- 1H-imidazol-4-yl)- N-(1-(methyl- sulfonyl)piperidin-4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 583.2 112 4-(1-(2-Fluoro-4- ((2-methoxyethyl)-amino)phenyl)-2- methyl-1H-imidazol- 4-yl)-N-(1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 572.2 113 2-((3-Fluoro-4- (2-methyl-4-(2-((1-(methyl- sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)-pyrimidin-4-yl)- 1H-imidazol-1- yl)phenyl)(methyl)- amino)ethan-1-ol

LCMS [M + H]: found 572.2 114 4-(1-(2-Fluoro-4- (4-(pyrrolidin-1-yl)piperidin-1-yl)- phenyl)-2-methyl- 1H-imidazol-4-yl)- N-(1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 651.3 115 (R)-4-(1-(2-Fluoro- 4-(3-methyl-piperazin-1-yl)- phenyl)-2-methyl- 1H-imidazol-4-yl)- N-(1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 597.2 116 (S)-1-(3-Fluoro-4- (2-methyl-4-(2-((1-(methylsulfonyl)- piperidin-4-yl)- amino)-5-(trifluoro-methyl)pyrimidin-4- yl)-1H-imidazol-1- yl)phenyl)pyrrolidin- 3-ol

LCMS [M + H]: found 584.2 117 (R)-4-(1-(2-Fluoro- 4-((1-methyl-piperidin-3-yl)- amino)phenyl)-2- methyl-1H-imidazol- 4-yl)-N-(1-methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 611.3

Example 118.4-(1-(4-(4-(Dimethylamino)piperidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 41, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 39) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 38) as starting material. LCMS calculated forC₂₁H₂₁F₅IN₆O₂S (M+H)⁺: m/z=643.0; Found 643.0.

Step 2:4-(1-(4-(4-(Dimethylamino)piperidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 101, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Step 1) instead of4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 41) as starting material. LCMS calculated forC₂₈H₃₆F₅N₈O₂S (M+H)⁺: m/z=643.3; Found 643.3.

Example 119.4-(1-(2-Chloro-4-(1-methyl-1H-pyrazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:4-(1-(4-Bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 42, using 2-chloro-1-fluoro-4-bromobenzene instead of2-chloro-1-fluoro-4-iodobenzene as starting material. LCMS calculatedfor C₂₀H₂₀BrClF₃N₆O₂S (M+H)⁺: m/z=579.0; Found 579.0.

Step 2:4-(1-(2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of4-(1-(4-bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.172mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (52.6mg, 0.207 mmol) and potassium acetate (42.3 mg, 0.431 mmol) in dioxane(0.575 mL) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (14.08 mg, 0.017 mmol). Themixture was purged with N₂, sealed and stirred at 100° C. for 2 h. Aftercompletion, the reaction was cooled to room temperature. The mixture wasconcentrated and the residue was purified by column chromatographyeluting with a gradient of hexanes/EtOAc (0-90%) on silica gel. LCMScalculated for C₂₆H₃₂BClF₃N₆O₄S (M+H)⁺: m/z=627.2; Found 627.2.

Step 3:4-(1-(2-Chloro-4-(I-methyl-1H-pyrazol-5-yl)phenyl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of4-(1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (15 mg, 0.024 mmol), 5-iodo-1-methyl-1H-pyrazole(14.93 mg, 0.072 mmol) and potassium phosphate (15.24 mg, 0.072 mmol) inwater (0.04 mL) and dioxane (0.20 mL) was addedchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.82 mg, 3.59 mol). The mixture was purged with N₂, sealed and stirredat 110° C. for 2h. After completion, the reaction was cooled to roomtemperature. The mixture was diluted with MeOH, filtered and purified byprep HPLC (pH=2). LCMS calculated for C₂₄H₂₅ClF₃N₈O₂S (M+H)⁺: m/z=581.2;Found 581.2.

TABLE 11 The compounds in Table 11 were prepared in accordance with thesynthetic protocols set forth in Example 119 using the appropriatehalides for Suzuki coupling in the last step. Analytical Ex. NameStructure data 120 4-(1-(2-Chloro-4-(1,4- dimethyl-1H-1,2,3-triazol-5-yl)phenyl)- 1H-imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 596.2 121 4-(1-(2-Chloro-4-(1- methyl-1H-1,2,4-triazol-5-yl)phenyl)- 1H-imidazol-4-yl)- N-(1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 582.1 122 4-(1-(2-Chloro-4-(1- methyl-1H-1,2,3-triazol-5-yl)phenyl)- 1H-imidazol-4-yl)- N-(1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 582.1 123 4-(1-(2-Chloro-4-(1,4-dimethyl-1H-imidazol- 5-yl)phenyl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)- piperidin-4-yl)-5- (trifluoromethyl)-pyrimidin-2-amine

LCMS [M + H]: found 595.2 124 4-(1-(2-Chloro-4-(1- methyl-1H-imidazol-5-yl)phenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 581.2

Example 125.5-(1-Methyl-1H-1,2,4-triazol-5-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

Step 1:5-Bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

To a solution of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(112 mg, 0.287 mmol) in acetonitrile (1.434 mL) was added5-bromo-2-fluorobenzonitrile (57.4 mg, 0.287 mmol) and cesium carbonate(280 mg, 0.861 mmol). The mixture was stirred at 80° C. for 4 h. Aftercooling to room temperature, the mixture was filtered and the filtratewas concentrated and used directly in the next step. LCMS calculated forC₂₁H₂₀BrF₃N₇O₂S (M+H)⁺: m/z=570.0; Found 570.0.

Step 2:2-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

This compound was prepared according to the procedures described inExample 119, Step 2, using5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrileinstead of4-(1-(4-bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₂₇H₃₂BF₃N₇O₄S (M+H)⁺:m/z=618.2; Found 618.2.

Step 3:5-(1-Methyl-1H-1,2,4-triazol-5-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 119, using2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileand 5-bromo-1-methyl-1H-1,2,4-triazole instead of4-(1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine and 5-iodo-1-methyl-1H-pyrazole as starting materialsfor the Suzuki coupling reaction. LCMS calculated for C₂₄H₂₄F₃N₁₀O₂S(M+H)⁺: m/z=573.2; Found 573.2.

Example 126.5-(Difluoromethoxy)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

To a solution of2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Example 125, Step 2, 14.8 mg, 0.024 mmol) in THF (0.24 mL) was addedsodium hydroxide (4.0 M aq. solution, 12.0 μL) and hydrogen peroxide(35% in water, 5 μL). The reaction was stirred at room temperature for 1h. Then to the mixture was added potassium hydroxide (26.8 mg, 0.479mmol) and diethyl (bromodifluoromethyl)phosphonate (8.50 μL, 0.048mmol). The reaction mixture was further stirred at room temperature for1 h. Then the reaction was diluted and filtered and purified by prepHPLC (pH=2). LCMS calculated for C₂₂H₂₁F₅N₇O₃S (M+H)⁺: m/z=558.1; Found558.2.

Example 127.4-(1-(4-(1,3-Dimethyl-1H-pyrazol-4-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(12 mg, 0.019 mmol),1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(8.54 mg, 0.038 mmol)), sodium carbonate (6.11 mg, 0.058 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium (II)dichloromethane adduct (3.5 mg) in water (0.032 mL) and dioxane (0.16mL) was purged with N₂ and then stirred at 100° C. overnight. Thereaction was cooled to room temperature. After cooling, the reactionmixture was then diluted with MeOH, filtered and the filtrate waspurified by prep HPLC (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₆H₂₉F₄N₈O₂S (M+H)⁺: m/z=593.2; Found 593.2.

Example 128.4-(1-(2-Fluoro-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:(3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)boronicacid

This compound was prepare according to the procedures described inExample 119, Step 2, using4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineinstead of4-(1-(4-bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₂₁H₂₄BF₄N₆O₄S (M+H)⁺:m/z=543.3; Found 543.3.

Step 2:4-(1-(2-Fluoro-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 119, Step 3, using(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)boronicacid and 4-bromo-1-methyl-1H-1,2,3-triazole instead of4-(1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine and 5-iodo-1-methyl-1H-pyrazole as starting materialsfor the Suzuki coupling reaction. LCMS calculated for C₂₄H₂₆F₄N₉O₂S(M+H)⁺: m/z=580.2; Found 580.2.

TABLE 12 The compound in Table 12 was prepared in accordance with thesynthetic protocols set forth in Example 128, using the appropriateheteroaryl halide for Suzuki coupling in the last step. Analytical Ex.Name Structure data 129 4-(1-(2-Fluoro-4-(1- methyl-1H-pyrazol-5-yl)phenyl)-2-methyl- 1H-imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 579.2

Example 130.6-Methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide

To a solution of6-methyl-1-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile(Example 33, 14 mg, 0.028 mmol) in ethanol (200 μL) and water (30 μL)was added hydrido(dimethylphosphinous acid-kP)[hydrogenbis(dimethylphosphinito-kP)]platinum(II) (0.3 mg). The mixture wasrefluxed at 100° C. in a sealed vial for 2h. After cooling to roomtemperature, the reaction mixture was diluted with MeOH, filtered andthe filtrate was purified by prep HPLC (Sunfire C18 column, eluting witha gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₁H₂₄F₃NO₃S (M+H)⁺: m/z=525.2; Found525.2.

Example 131.6-Methyl-N-(methyl-d)-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide

Step 1: 5-Fluoro-6-methyl-N-(methyl-d₃)picolinamide

A mixture of 5-fluoro-6-methylpicolinic acid (20 mg, 0.129 mmol),Hunig's base (90 μL, 0.516 mmol), and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (63.7 mg, 0.168 mmol) in DCM (0.5 mL) wasstirred at room temperature for 20 min, then the methan-d3-aminehydrochloride (9.09 mg, 0.129 mmol) was added and the solution wasstirred for 1 h. After completion, the reaction was quenched with water.The organic layer was separated using a phase separator and the filtratewas concentrated. The residue was used directly without furtherpurification. LCMS calculated for C₈H₇D₃FN₂O (M+H)⁺: m/z=172.1; Found172.1.

Step 2:6-Methyl-N-(methyl-d₃)-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide

A mixture of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(8 mg, 0.020 mmol), 5-fluoro-6-methyl-N-(methyl-d₃)picolinamide (3.51mg, 0.020 mmol) and cesium carbonate (26.7 mg, 0.082 mmol) in anhydrousDMF (0.068 mL) was heated at 110° C. for 1 h. After cooling, thereaction mixture was dissolved in MeOH, filtered and purified by prepHPLC (pH=2). LCMS calculated for C₂₂H₂₃D₃F₃N₈O₃S (M+H)⁺: m/z=542.2;Found 542.2.

TABLE 13 The compounds in Table 13 were prepared in accordance with thesynthetic protocols set forth in Example 131, using the appropriateamines for amide coupling in step 1. Analytical Ex. Name Structure data132 N,6-Dimethyl-5- (4-(2-((1-(methyl- sulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)- pyrimidin-4-yl)- 1H-imidazol-1-yl)picolinamide

LCMS [M + H]: found 539.2 133 N-Isopropyl-6- methyl-5-(4-(2-((1-(methyl- sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)-pyrimidin-4-yl)- 1H-imidazol-1- yl)picolinamide

LCMS [M + H]: found 567.2 134 N-Ethyl-6-methyl- 5-(4-(2-((1-(methyl-sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1- yl)picolinamide

LCMS [M + H]: found 553.2

Example 135.3-Chloro-N,N-dimethyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzamide

This compound was prepared according to the procedures described inExample 131, using 3-chloro-4-fluorobenzoic acid and dimethylamineinstead of 5-fluoro-6-methylpicolinic acid and methan-d₃-aminehydrochloride as starting material for step 1. LCMS calculated forC₂₃H₂₆ClF₃N₇O₃S (M+H)⁺: m/z=572.2; Found 572.2.

Example 136.3-Chloro-2-fluoro-N,N-dimethyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzamide

This compound was prepared according to the procedures described inExample 131, using 3-chloro-2,4-difluorobenzoic acid and dimethylamineinstead of 5-fluoro-6-methylpicolinic acid and methan-d₃-aminehydrochloride as starting material for step 1. LCMS calculated forC₂₃H₂₅ClF₄N₇O₃S (M+H)⁺: m/z=590.1; Found 590.1.

Example 137.2,3-Dichloro-N-methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzamide

This compound was prepared according to the procedures described inExample 131, using 2,3-dichloro-4-difluorobenzoic acid and methylamineinstead of 5-fluoro-6-methylpicolinic acid and methan-d₃-aminehydrochloride as starting material for step 1. LCMS calculated forC₂₂H₂₃Cl₂F₃N₇O₃S (M+H)⁺: m/z=592.1; Found 592.1.

Example 138.(R)-1-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)pyrrolidin-3-ol

This compound was prepared according to the procedures described inExample 101, using4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 42) instead of4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 41) as starting material. LCMS calculated forC₂₄H₂₈ClF₃N₇O₃S (M+H)⁺: m/z=586.2; Found 586.2.

TABLE 14 The compounds in Table 14 were prepared in accordance with thesynthetic protocols set forth in Example 138, using the appropriateamine as starting material. Analytical Ex. Name Structure data 139(S)-1-(3-Chloro-4- (4-(2-((1-(methyl- sulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)- pyrimidin-4-yl)- 1H-imidazol-1-yl)-phenyl)pyrrolidin- 3-ol

LCMS [M + H]: found 586.2 140 (S)-4-(1-(2-Chloro- 4-(3-methyl-piperazin-1-yl)- phenyl)-1H- imidazol-4-yl)- N-(1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 599.2 141 (R)-4-(1-(2-Chloro- 4-(3-methyl-piperazin-1-yl)- phenyl)-1H- imidazol-4-yl)- N-(1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 599.2 142 4-(3-Chloro-4-(4- (2-((1-(methyl-sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1- yl)phenyl)-1- methylpiperazin- 2-one

LCMS [M + H]: found 613.2 143 4-(1-(2-Chloro-4- (3-(dimethylamino)-pyrrolidin-1-yl)- phenyl)-1H- imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 613.2 144 4-(1-(2-Chloro-4- ((2-methoxyethyl)-amino)phenyl)-1H- imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 574.2 145 4-(1-(2-Chloro-4- (4-(dimethylamino)-piperidin-1-yl)- phenyl)-1H- imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 627.2 146 4-(1-(2-Chloro-4- (4-(pyrrolidin-1-yl)piperidin-1-yl)- phenyl)-1H- imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 653.2 147 1-(3-Chloro-4-(4- (2-((1-(methyl-sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1-yl)- phenyl)-3-methyl- imidazolidin-2-one

LCMS [M + H]: found 599.2 148 4-(1-(2-Chloro-4-(4- methylpiperazin-1-yl)phenyl)-1H- imidazol-4-yl)-N- (1-(methylsulfonyl)- piperidin-4-yl)-5-(trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 599.2 149 N¹-(3-Chloro-4-(4- (2-((1-(methyl-sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)-pyrimidin-4-yl)-1H- imidazol-1-yl)- phenyl)-N1,N2,N2- trimethylethane-1,2-diamine

LCMS [M + H]: found 601.2 150 4-(3-Chloro-4-(4- (2-((1-(methyl-sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1-yl)- phenyl)piperazin- 2-one

LCMS [M + H]: found 599.2

Example 151.4-(1-(2-Chloro-4-methoxyphenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(15 mg, 0.024 mmol), cesium carbonate (11.70 mg, 0.036 mmol),3,4,7,8-tetramethyl-1,10-phenanthroline (0.566 mg, 2.393 μmol) andcopper(I) iodide (0.228 mg, 1.197 μmol) in toluene (0.120 mL) was addedmethanol (7.67 mg, 0.239 mmol). The mixture was degassed with N₂ andthen sealed, and stirred at 100° C. overnight. After completion, thereaction was cooled to room temperature. The mixture was diluted withMeOH, filtered and purified by prep HPLC (Sunfire C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). LCMS calculated for C₂₁H₂₃ClF₃N₆O₃S (M+H)⁺: m/z=531.1;Found 531.1.

Example 152.6-Methyl-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

Step 1: tert-Butyl(3R,4S)-4-((4-(1-(2-cyano-6-methylpyridin-3-yl)-H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate

To a solution of tert-butyl(3R,4S)-4-((4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate (Intermediate 24,0.225 g, 0.528 mmol) in acetonitrile (5.28 mL) was added3-fluoro-6-methylpicolinonitrile (0.086 g, 0.633 mmol) and cesiumcarbonate (0.516 g, 1.583 mmol). The mixture was stirred at 80° C. for 1h. After cooling to room temperature, the reaction was diluted withacetonitrile and filtered through a short pad of celite. The filtratewas concentrated and the residue was used directly without furtherpurification. LCMS calculated for C₂₆H₃F₃N₈O₂ (M+H)⁺: m/z=543.2; Found543.2.

Step 2:6-Methyl-3-(4-(2-(((3R,4S)-3-methylpiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

To a solution of tert-butyl(3R,4S)-4-((4-(1-(2-cyano-6-methylpyridin-3-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate(the residue in Step 1) in THF (5.0 mL) was added HCl (4M in dixoane,0.40 mL). The mixture was stirred at 90° C. for 1 h. After cooling toroom temperature, the mixture was diluted with water (15 mL) and thenwashed by Et₂O three times. The aqueous layer was separated andneutralized by addition of sodium hydroxide pellets until pH=6-7. Theneutralized aqueous layer was then extracted with DCM three times. Theorganic layers were combined and dried over MgSO₄. After filtration, thefiltrate was concentrated and the residue was used directly withoutfurther purification. LCMS calculated for C₂₁H₂₂F₃N₈ (M+H)⁺: m/z=443.2;Found 443.2.

Step 3:6-Methyl-3-(4-(2-(((3R,4S)-3-methyl-1-((I-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

To a solution of6-methyl-3-(4-(2-(((3R,4S)-3-methylpiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrilehydrochloride (10 mg, 0.021 mmol) in CH₂Cl₂ (0.20 mL) was addedtriethylamine (15 μL) and 1-methyl-1H-imidazole-4-sulfonyl chloride (4.5mg, 0.025 mmol) at 0° C. The mixture was stirred at room temperature for1 h. Then the reaction was concentrated and diluted with MeOH, which waspurified by prep HPLC (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₅H₂₆F₃N₁₀O₂S (M+H)⁺: m/z=587.2; Found 587.2.

TABLE 15 The compounds in Table 15 were prepared in accordance with thesynthetic protocols set forth in Example 152, using the appropriatesulfonyl chlorides in step 3. Analytical Ex. Name Structure data 1533-(4-(2-(((3R,4S)- 1-((2-Amino- pyrimidin-5-yl)- sulfonyl)-3-methylpiperidin- 4-yl)amino)-5- (trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1- yl)-6-methyl- picolinonitrile

LCMS [M + H]: found 600.2 154 6-Methyl-3-(4- (2-(((3R,4S)-3-methyl-1-((1- methyl-1H- pyrazol-3-yl)- sulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)- pyrimidin-4-yl)- 1H-imidazol-1-yl)picolinonitrile

LCMS [M + H]: found 587.2

Example 155.2-Chloro-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

Step 1:N,N-Dimethyl-4-(2-(((3R,4S)-3-methylpiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamide

This compound was prepared from Boc deprotection (according to theprocedure described in Example 152, step 2) of tert-butyl(3R,4S)-4-((4-(1-(N,N-dimethylsulfamoyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate,which is the Suzuki coupling product described in the Intermediate 23procedure. LCMS calculated for C₁₆H₂₃F₃N₇O₂S (M+H)⁺: m/z=434.2; Found434.2.

Step 2:N,N-Dimethyl-4-(2-(((3R,4S)-3-methyl-1-((I-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamide

To a solutionN,N-dimethyl-4-(2-(((3R,4S)-3-methylpiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamide(180 mg, 0.415 mmol) in DCM (2.1 mL) was added1-methyl-1H-imidazole-4-sulfonyl chloride (75 mg, 0.415 mmol) andtriethylamine (180 μL, 1.25 mmol) at 0° C. The mixture was stirred atroom temperature for 1 h. Then the reaction was concentrated and theresidue was purified by column chromatography on silica gel to affordN,N-dimethyl-4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamide.LCMS calculated for C₂₀H₂₇F₃N₉O₄S₂ (M+H)⁺: m/z=578.2; Found 578.3.

Step 3:4-(H-Imidazol-4-yl)-N-((3R,4S)-3-methyl-1-((I-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar,N,N-dimethyl-4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamide(200 mg) was dissolved in EtOH (2 mL). Concentrated HCl (0.2 mL) wasadded to the mixture at room temperature, then the solution was heatedat 70° C. for 2 hours. After the completion, the mixture was cooled toroom temperature, then water was added (15 mL). The resultant solutionwas washed with Et₂O. The aqueous phase was neutralized by NaOH (solid)and adjusted to pH 6-7. The product in the aqueous phase was extractedby DCM/MeOH (10/1 ratio) three times. The filtrate was dried over Na₂SO₄and concentrated. The residue was purified by column chromatography onsilica gel to afford4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine.LCMS calculated for C₁₈H₂₂F₃N₈O₂S (M+H)⁺: m/z=471.1; Found 471.1.

Step 4:2-Chloro-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

To a mixture of4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(10 mg, 0.021 mmol) and triethylamine (14.81 μL, 0.106 mmol) in DCM(0.21 mL) was added 2-chloro-3-fluorobenzonitrile (3.31 mg, 0.021 mmol).The mixture was stirred at room temperature for 30 min. Then thereaction was concentrated and diluted with MeOH, which was purified byprep HPLC (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₅H₂₄ClF₃N₉O₂S (M+H)⁺: m/z=606.1; Found 606.1.

Example 156.4-(1-(5-Bromoquinoxalin-6-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 22, 12 mg, 0.030 mmol), 5-bromo-6-fluoroquinoxaline (20.2mg, 0.089 mmol) and cesium carbonate (48.3 mg, 0.148 mmol) was added DMF(0.15 mL). The mixture was stirred at 110° C. for 2 h. After cooling toroom temperature, the resultant mixture was diluted with MeOH, and thenfiltered. The filtrate was purified by prep HPLC (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₃H₂₃BrF₃N₈O₂S (M+H)⁺:m/z=611.1; Found 611.1.

Example 157.4-(1-(2-Chloro-4-(2-(dimethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:4-(1-(4-Allyl-2-chlorophenyl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 42, 250 mg, 0.40 mmol),2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (335 mg, 2.0 mmol),cesium fluoride (182 mg, 1.2 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium (II)dichloromethane adduct (32.6 mg, 0.04 mmol) in water (0.57 mL) anddioxane (2.85 mL) was purged with N₂ and then stirred at 100° C. for 2h. The reaction was cooled to room temperature. The reaction mixture wasdiluted with dichloromethane and then washed with H₂O and brinesolution. The organic layer was dried MgSO₄, filtered and the filtratewas concentrated to give a crude residue, which was purified by flashchromatography eluting with a gradient of hexanes/EtOAc (0 to 80%) on asilica gel column. LCMS calculated for C₂₃H₂₅ClF₃N₆O₂S (M+H)⁺:m/z=541.1; Found 541.1.

Step 2:2-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)acetaldehyde

To a vial was added sodium periodate (427 mg, 1.994 mmol), potassiumosmate dihydrate (7.35 mg, 0.020 mmol) and4-(1-(4-allyl-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(from Step 1) in THF (2.85 mL) and water (0.570 mL). The mixture wasstirred at room temperature for 1 h. Then the mixture was diluted withwater and extracted with DCM three times. The organic layers werecombined and dried over MgSO₄. After filtration, the filtrate wasconcentrated and the residue was purified by column chromatography witha gradient of DCM/MeOH (0 to 15%) on silica gel. LCMS calculated forC₂₂H₂₃ClF₃N₆O₃S (M+H)⁺: m/z=543.2; Found 543.2.

Step 3:4-(1-(2-Chloro-4-(2-(dimethylamino)ethyl)phenyl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of2-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)acetaldehyde(13 mg, 0.024 mmol), dimethylamine (35.9 μL, 0.072 mmol, 2.OM in THF)and acetic acid (2.74 μL, 0.048 mmol) in DCM (0.160 mL) was stirred atroom temperature for 30 min. Then sodium triacetoxyborohydride (10.15mg, 0.048 mmol) was added. The mixture was further stirred at roomtemperature for 1 h. The reaction was concentrated. The residue was thendiluted with MeOH, filtered and the filtrate was purified by prep HPLC(Sunfire C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60m/min). LC-MS calculated forC₂₄H₃₀ClF₃N₇O₂S (M+H)⁺: m/z=572.2; found 572.2.

TABLE 16 The compounds in Table 16 were prepared in accordance with thesynthetic protocols set forth in Example 157, using the appropriateamines for reductive amination in the last step. Analytical Ex. NameStructure data 158 4-(1-(4-(2-(Azetidin- 1-yl)ethyl)-2-chloro-phenyl)-1H-imidazol- 4-yl)-N-(1-(methyl- sulfonyl)piperidin-4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 584.2 159 4-(3-Chloro-4-(4-(2- ((1-(methylsulfonyl)-piperidin-4-yl)- amino)-5-(trifluoro- methyl)pyrimidin-4-yl)-1H-imidazol- 1-yl)phenethyl)-1- methylpiperazin- 2-one

LCMS [M + H]: found 641.2

Example 160.4-(1-(4-(Azetidin-3-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of zinc dust (3.15 mg, 0.048 mmol), 1,2-dibromoethane(0.277 μL, 3.21 μmol) and TMSCl (0.408 μL, 3.21 μmol) was added THF(0.161 mL). The mixture was sparged with N₂ and then stirred at 60° C.in a sealed vial. After 15 minutes, to the mixture was added tert-butyl3-iodoazetidine-1-carboxylate (9.10 mg, 0.032 mmol) inN,N-dimethylacetamide (0.16 mL). The mixture continued to stir at 60° C.for an additional 15 minutes. Then after the reaction was cooled to roomtemperature, to the mixture was added4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(20.07 mg, 0.032 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (1.312 mg, 1.607 μmol) and CuI(0.306 mg, 1.607 μmol). The mixture was purged with N₂ and stirred at80° C. overnight. After cooling to room temperature, the mixture wasfiltered through a short pad of celite and the filtrate wasconcentrated. The residue was then dissolved in DCM (0.20 mL) andtreated with trifluoroacetic acid (0.40 mL). The mixture was stirred atroom temperature for 30 min. The reaction was concentrated and dilutedwith MeOH, then was purified by prep HPLC (Sunfire C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min). LCMS calculated for C₂₄H₂₈F₄N₇O₂S (M+H)⁺: m/z=554.2;Found 554.2.

TABLE 17 The compound in Table 17 was prepared in accordance with thesynthetic protocols set forth in Example 160, using the appropriatealkyl iodides for the coupling reaction in the last step. Analytical Ex.Name Structure data 161 4-(1-(2-Fluoro-4- (1-methylpiperidin-4-yl)phenyl)-2- methyl-1H-imidazol- 4-yl)-N-(1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin- 2-amine

LCMS [M + H]: found 596.2

Example 162.4-(1-(5-Bromoquinoxalin-6-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2, 8 mg, 0.020 mmol), 5-bromo-6-fluoroquinoxaline (6.98mg, 0.031 mmol) and cesium carbonate (26.7 mg, 0.082 mmol) in anhydrousDMF (0.068 mL) was heated at 120° C. for 2 h. After cooling, thereaction mixture was then diluted with MeOH, filtered and the filtratewas purified by prep HPLC (Sunfire C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LCMS calculated for C₂₂H₂BrF₃N₈O₂S (M+H)⁺: m/z=597.1; Found 597.1.

TABLE 18 The compounds in Table 18 were prepared in accordance with thesynthetic protocols set forth in Example 162, using the appropriateheteroaryl halides for the S_(N)Ar reaction. Analytical Ex. NameStructure data 163 4-(1-(8-Bromoquinolin- 7-yl)-1H-imidazol-4-yl)-N-(1-(methyl- sulfonyl)piperidin-4- yl)-5-(trifluoromethyl)-pyrimidin-2-amine

LCMS [M + H]: found 596.1 164 4-(1-(5-Bromoquinolin-6-yl)-1H-imidazol-4- yl)-N-(1-(methyl- sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 596.1 165 4-(1-(8-Chloroquinolin-7-yl)-1H-imidazol-4- yl)-N-(1-(methyl- sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)- pyrimidin-2-amine

LCMS [M + H]: found 552.1

Example 166.4-(1-(5-Methylquinoxalin-6-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of4-(1-(5-bromoquinoxalin-6-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 162, 28 mg, 0.046 mmol),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (23.15 mg, 0.184 mmol),potassium carbonate (15.93 mg, 0.115 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (7.53 mg, 9.22 μmol) in water (0.05 mL) anddioxane (0.25 mL) was purged with N₂ and then stirred at 100° C.overnight. The reaction was cooled to room temperature. After cooling,the reaction mixture was then diluted with MeOH, filtered and thefiltrate was purified by prep HPLC (Sunfire C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60m/min). LCMS calculated for C₂₃H₂₄F₃N₈O₂S (M+H)⁺: m/z=533.2; Found533.2.

Example 167.6-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)quinoxaline-5-carbonitrile

To a mixture of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2, 15 mg, 0.038 mmol), 5-bromo-6-fluoroquinoxaline (13.1mg, 0.058 mmol) and cesium carbonate (37.6 mg, 0.115 mmol) was added DMF(0.4 mL). The mixture was heated at 100° C. for 1 h. The reaction wasthen cooled to room temperature and filtered to remove insolubles. Tothe filtrate was added zinc cyanide (4.5 mg, 0.038 mmol) andtetrakis(triphenylphosphine)palladium(O) (9 mg, 7.68 μmol). The mixturewas sparged with N₂ and stirred at 120° C. in a sealed vial overnight.After cooling to room temperature, the reaction mixture was diluted withMeOH, filtered and the filtrate was purified by prep HPLC (Sunfire C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₃H₂₁F₃N₉O₂S(M+H)⁺: m/z=544.2; Found 544.2.

Example 168.4-Methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

To a mixture of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2, 15 mg, 0.038 mmol), 5-chloro-4-methylpicolinonitrile(17.59 mg, 0.115 mmol) and cesium carbonate (62.6 mg, 0.192 mmol) wasadded DMF (0.128 mL). The mixture was stirred at 100° C. for 2 hrs. Thecrude solution was diluted with MeCN and MeOH after cooling to roomtemperature. The diluted solution was filtered and purified by prep HPLC(pH=2). LCMS calculated for C₂₁H₂₂F₃N₈O₂S (M+H)⁺: m/z=507.2; Found507.3.

Example 169.4-(1-(1,3-Dimethyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(15 mg, 0.038 mmol), 4-iodo-1,3-dimethyl-1H-pyrazole (25.6 mg, 0.115mmol), cesium carbonate (37.6 mg, 0.115 mmol), copper(I) oxide (0.550mg, 3.84 μmol), and salicylaldoxime (1.054 mg, 7.68 μmol) in a vial wasadded DMF (0.20 mL). The mixture was degassed by N₂. Then the sealedvial was stirred at 150° C. overnight. After cooling to roomtemperature, the mixture was diluted with MeOH and MeCN, and filtered.The filtrate was purified by prep HPLC (pH=2). LCMS calculated forC₁₉H₂₄F₃N₈O₂S (M+H)⁺: m/z=485.2; Found 485.2.

Example 170.3-Chloro-4-(5-chloro-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

In a vial with a stir bar, a mixture of3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile(Example 1, 16 mg, 0.030 mmol) and N-chlorosuccinimide (8.1 mg, 0.060mmol) was stirred at room temperature for 16 hours. After the resultantmixture was concentrated under reduced pressure, the material obtainedwas dissolved in methanol and purified by prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). ¹H NMR (TFA salt, 500 MHz, DMSO-d₆) δ 8.71 (s,0.33H), 8.65 (s, 0.67H), 8.47 (s, 1H), 8.20 (s, 0.67H), 8.18 (s, 0.33H),8.15-8.05 (m, 2H), 8.02 (d, J=8.2 Hz, 0.67H), 7.94 (d, J=8.2 Hz, 0.33H),4.03-3.93 (m, 1H), 3.58-3.47 (m, 2H), 2.91-2.73 (m, 5H), 2.03-1.92 (m,2H), 1.64-1.49 (m, 2H). LCMS calculated for C₂₁H₉Cl₂F₃N₇O₂S (M+H)⁺:m/z=560.1; Found 560.1.

TABLE 19 The compounds in Table 19 were prepared in accordance with thesynthetic protocols set forth in Example 1 using the appropriatestarting materials. Analytical Ex. Name Structure data 1713-Chloro-4-(4-(5- chloro-2-((1- (methylsulfonyl)- piperidin-4-yl)-amino)pyrimidin- 4-yl)-1H-imidazol- 1-yl)benzonitrile

LCMS found 492.1 172 3-Chloro-4-(4-(2- (((3R,4S)-3-methyl-1-(methylsulfonyl)- piperidin-4-yl)- amino)-5-(trifluoro-methyl)pyrimidin-4- yl)-1H-imidazol-1- yl)benzonitrile

LCMS found 540.1 173 3-Chloro-4-(4-(2- (((3R,4R)-3-fluoro-1-(methylsulfonyl)- piperidin-4-yl)- amino)-5-(trifluoro-methyl)pyrimidin-4- yl)-1H-imidazol-1- yl)benzonitrile

LCMS found 544.2

Example 174.N-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-N-methylacetamide

In a vial with a stir bar, a mixture of4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Example 3, 10 mg, 0.018 mmol), acetic acid (0.50 mL, 8.7 mmol), andtriethylamine (1.50 mL, 10.8 mmol) was stirred at room temperature for 6hours. After the resultant mixture was concentrated under reducedpressure, the material obtained was dissolved in methanol and purifiedby prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₂₈ClF₃N₇O₃S (M+H)⁺: m/z=586.2; Found 586.1.

Example 175.4-(1-(2-Chloro-4-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, a mixture of3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde(Step 1 in Example 3, 140 mg, 0.260 mmol), dimethylamine (2 M in THF,1.3 mL, 2.6 mmol), acetic acid (0.10 mL, 1.7 mmol), triethylamine (0.10mL, 0.72 mmol), MeOH (10 mL), and THF (10 mL) was stirred at 70° C. for1 hour. After the solution was cooled to room temperature, NaCNBH₃ (200mg, 3.2 mmol) was added to the resultant mixture. The solution wasstirred at room temperature for 30 minutes, and then at 60° C. for 30minutes. The resultant mixture was concentrated under reduced pressure.The residue was dissolved in MeOH and purified by prep-LCMS (Sunfire C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). ¹H NMR (TFA salt, 600 MHz, DMSO-d₆, 1:1rotamers) δ 10.1 (brs, 1H), 8.66 (s, 0.5H), 8.60 (s, 0.5H), 8.20 (s,0.5H), 8.11 (s, 1H), 8.01 (s, 0.5H), 7.97-7.87 (m, 2H), 7.85-7.73 (m,1H), 7.70-7.61 (m, 1H), 4.39 (s, 2H), 4.09-3.91 (m, 1H), 3.59-3.45 (m,2H), 2.97-2.82 (m, 5H), 2.78 (s, 6H), 2.00-1.91 (m, 2H), 1.63-1.54 (m,2H). LCMS calculated for C₂₃H₂₈ClF₃N₇O₂S (M+H)⁺: m/z=558.2; Found 558.3.

Example 176.4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 175, using azetidine hydrochloride instead of dimethylamine (2 Min THF) as starting material. ¹H NMR (TFA salt, 600 MHz, DMSO-d₆, 1:1rotamers) δ 10.4 (brs, 1H), 8.65 (s, 0.5H), 8.59 (s, 0.5H), 8.20 (s,0.5H), 8.11-8.09 (m, 1H), 7.99 (s, 0.5H), 7.96-7.82 (m, 2H), 7.82-7.71(m, 1H), 7.66-7.57 (m, 1H), 4.46 (s, 2H), 4.19-3.92 (m, 5H), 3.60-3.45(m, 2H), 2.94-2.80 (m, 5H), 2.47-2.27 (m, 2H), 2.00-1.91 (m, 2H),1.64-1.52 (m, 2H). LCMS calculated for C₂₄H₂₈ClF₃N₇O₂S (M+H)⁺:m/z=570.2; Found 570.2.

Example 177.4-(1-(2-Chloro-4-((3-methylazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 175, using 3-methylazetidine hydrochloride instead ofdimethylamine (2 M in THF) as starting material. ¹H NMR (TFA salt, 500MHz, DMSO-d₆, 4:6 rotamers) δ 10.1 (brs, 1H), 8.66 (s, 0.4H), 8.59 (s,0.6H), 8.19 (s, 0.6H), 8.09 (s, 1H), 7.99 (s, 0.4H), 7.96-7.83 (m, 2H),7.83-7.72 (m, 1H), 7.67-7.58 (m, 1H), 4.48 (d, J=5.9 Hz, 0.8H), 4.43 (d,J=5.6 Hz, 1.2H), 4.23-4.14 (m, 0.8H), 4.12-3.92 (m, 2.2H), 3.84 (dd,J=9.1, 9.1 Hz, 1.2H), 3.77-3.68 (m, 0.8H), 3.60-3.46 (m, 2H), 2.95-2.76(m, 6H), 2.01-1.90 (m, 2H), 1.65-1.52 (m, 2H), 1.24 (d, J=7.0 Hz, 1.2H),1.18 (d, J=6.7 Hz, 1.8H). LCMS calculated for C₂₅H₃₀ClF₃N₇O₂S (M+H)⁺:m/z=584.2; Found 584.2.

Example 178.4-(1-(2-Chloro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 175, using pyrrolidine instead of dimethylamine (2 M in THF) asstarting material. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1 rotamers) δ9.92 (brs, 1H), 8.66 (s, 0.5H), 8.60 (s, 0.5H), 8.19 (s, 0.5H),8.14-8.06 (m, 1H), 8.00 (s, 0.5H), 7.97-7.86 (m, 2H), 7.85-7.74 (m, 1H),7.72-7.63 (m, 1H), 4.53-4.38 (m, 2H), 4.08-3.91 (m, 1H), 3.61-3.47 (m,2H), 3.47-3.35 (m, 2H), 3.20-3.07 (m, 2H), 2.95-2.79 (m, 5H), 2.12-2.00(m, 2H), 2.00-1.93 (m, 2H), 1.93-1.82 (m, 2H), 1.65-1.53 (m, 2H). LCMScalculated for C₂₅H₃₀ClF₃N₇O₂S (M+H)⁺: m/z=584.2; Found 584.2.

Example 179.4-(1-(4-((2-Azabicyclo[2.2.2]octan-2-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 175, using 2-azabicyclo[2.2.2]octane instead of dimethylamine (2M in THF) as starting material. LCMS calculated for C₂₈H₃₄ClF₃N₇O₂S(M+H)⁺: m/z=624.2; Found 624.2.

Example 180.4-(1-(4-((2-Azabicyclo[2.2.1]heptan-2-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 175, using 2-aza-bicyclo[2.2.1]heptane instead of dimethylamine(2 M in THF) as starting material. LCMS calculated for C₂₇H₃₂ClF₃N₇O₂S(M+H)⁺: m/z=610.2; Found 610.2.

Example 181.(R)-1-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol

This compound was prepared according to the procedures described inExample 175, using (R)-3-methylpyrrolidin-3-ol hydrochloride instead ofdimethylamine (2 M in THF) as starting material. ¹H NMR (TFA salt, 600MHz, DMSO-d₆, 6:4 rotamers) δ 10.4 (brs, 0.6H), 10.3 (brs, 0.4H), 8.66(s, 0.4H), 8.60 (s, 0.6H), 8.20 (s, 0.6H), 8.10 (s, 1H), 8.00 (s, 0.4H),7.98-7.86 (m, 2H), 7.84-7.73 (m, 1H), 7.73-7.67 (m, 1H), 5.34 (brs, 1H),4.58-4.35 (m, 2H), 4.08-3.92 (m, 1H), 3.65-3.06 (m, 6H), 2.96-2.80 (m,5H), 2.17-1.81 (m, 4H), 1.64-1.52 (m, 2H), 1.40-1.28 (m, 3H). LCMScalculated for C₂₆H₃₂ClF₃N₇O₃S (M+H)⁺: m/z=614.2; Found 614.2.

Example 182.4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepare according to the procedures described inExample 3, using4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 22) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2) as starting material for Step 1. LCMS calculated forC₂₃H₂₈ClF₃N₇O₂S (M+H)⁺: m/z=558.2; Found 558.1.

Example 183.4-(1-(2-Chloro-4-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:3-Chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde

This compound was prepared according to the procedures described inExample 3, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2) as starting material for Step 1. LCMS calculated forC₂₁H₂₀ClF₄N₆O₃S (M+H)⁺: m/z=547.1; Found 547.1.

Step 2:4-(1-(2-Chloro-4-((dimethylamino)methyl)phenyl)-H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 175, using3-chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehydeinstead of3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde(Step 1 in Example 3) as starting material. LCMS calculated forC₂₃H₂₇ClF₄N₇O₂S (M+H)⁺: m/z=576.2; Found 576.1.

Example 184.4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 183, using azetidine hydrochloride instead of dimethylamine asstarting material for Step 2. LCMS calculated for C₂₄H₂₇ClF₄N₇O₂S(M+H)⁺: m/z=588.2; Found 588.2.

Example 185.N-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)acetamide

Step 1:4-(1-(4-(Aminomethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 175, using ammonia (0.4M in dioxane) instead of dimethylamine asstarting material. LCMS calculated for C₂₁H₂₄ClF₃N₇O₂S (M+H)⁺:m/z=530.1; Found 530.1.

Step 2:N-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)acetamide

This compound was prepared according to the procedures described inExample 174, using4-(1-(4-(aminomethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Step 1) instead of4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Example 3) as starting material. LCMS calculated for C₂₃H₂₆ClF₃N₇O₃S(M+H)⁺: m/z=572.1; Found 572.1.

TABLE 20 The compounds in Table 20 were prepared in accordance with thesynthetic protocols set forth in Example 175 using the appropriatestarting materials. Analytical Ex. Name Structure data 1864-(1-(2-Chloro-4- (((2,2-difluoroethyl)- amino)methyl)phenyl)-1H-imidazol-4-yl)-N- (1-(methylsulfonyl)- piperidin-4-yl)-5-(trifluoromethyl)- pyrimidin-2-amine

LCMS found 594.2 187 2-((3-Chloro-4-(4-(2- ((1-(methylsulfonyl)-piperidin-4-yl)amino)- 5-(trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)- amino)acetonitrile

LCMS found 569.2 188 4-(1-(2-Chloro-4- (((2,2,2-trifluoroethyl)-amino)methyl)phenyl)- 1H-imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS found 612.2 189 4-(1-(2-Chloro-4- ((ethylamino)methyl)-phenyl)-1H-imidazol- 4-yl)-N-(1-(methyl- sulfonyl)piperidin-4-yl)-5-(trifluoro- methyl)pyrimidin-2- amine

LCMS found 558.3   ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1 rotamers) δ8.87 (brs, 2H), 8.70- 8.55 (m, 1H), 8.18 (s, 0.5H), 8.10 (s, 1H), 7.99(s, 0.5H), 7.96-7.84 (m, 2H), 7.83-7.70 (m, 1H), 7.69-7.59 (m, 1H), 4.26(s, 2H), 4.09- 3.90 (m, 1H), 3.62- 3.43 (m, 2H), 3.08- 2.77 (m, 7H),2.03- 1.88 (m, 2H), 1.65- 1.51 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H) 1904-(1-(2-Chloro-4- ((cyclopropylamino)- methyl)phenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)- piperidin-4-yl)-5-(trifluoromethyl)- pyrimidin-2-amine

LCMS found 570.3 191 4-(1-(2-Chloro-4- (((cyclopropylmethyl)-amino)methyl)phenyl)- 1H-imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS found 584.3 192 4-(1-(2-Chloro-4- ((ethyl(methyl)amino)-methyl)phenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)-piperidin-4-yl-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS found 572.2 193 4-(1-(2-Chloro-4- ((3,3-difluoroazetidin-1-yl)methyl)phenyl)- 1H-imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS found 606.2 194 1-(3-Chloro-4-(4-(2- ((1-(methylsulfonyl)-piperidin-4-yl)amino)- 5-(trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)- 3-methylazetidin-3-ol

LCMS found 600.2 195 4-(1-(2-Chloro-4-((3- methoxyazetidin-1-yl)methyl)phenyl)- 1H-imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS found 600.2 196 4-(1-(2-Chloro-4- ((3-fluoro-3-methyl-azetidin-1-yl)methyl)- phenyl)-1H-imidazol- 4-yl)-N-(1-(methyl-sulfonyl)piperidin-4- yl)-5-(trifluoromethyl)- pyrimidin-2-amine

LCMS found 602.1 197 4-(1-(2-Chloro-4- ((3-fluoroazetidin-1-yl)methyl)phenyl)- 1H-imidazol-4-yl)- N-(1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin-2- amine

LCMS found 588.1 198 1-(3-Chloro-4-(4-(2- ((1-(methylsulfonyl)-piperidin-4-yl)amino)- 5-(trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)- azetidine-3-carbonitrile

LCMS found 595.2 199 1-(3-Chloro-4-(4-(2- ((1-(methylsulfonyl)-piperidin-4-yl)amino)- 5-(trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)- azetidin-3-ol

LCMS found 586.1 200 4-(1-(2-Chloro- 4-((3,3-dimethyl-azetidin-1-yl)methyl)- phenyl)-1H-imidazol- 4-yl)-N-(1-(methyl-sulfonyl)piperidin-4- yl)-5-(trifluoromethyl)- pyrimidin-2-amine

LCMS found 598.2 201 (1-(3-Chloro-4-(4-(2- ((1-(methylsulfonyl)-piperidin-4-yl)amino)- 5-(trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)- 2-methylazetidin-2- yl)methanol

LCMS found 614.1 202 2-(3-Chloro-4-(4-(2- ((1-(methylsulfonyl)-piperidin-4-yl)amino)- 5-(trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)- 2-azaspiro[3.3]heptan- 6-ol

LCMS found 626.2 203 2-(1-(3-Chloro-4- (4-(2-((1-(methyl-sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)-pyrimidin-4-yl)-1H- imidazol-1-yl)- benzyl)azetidin-3- yl)propan-2-ol

LCMS found 628.2 204 (S)-1-(3-Chloro-4- (4-(2-((1-(methyl-sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)-pyrimidin-4-yl)-1H- imidazol-1-yl)- benzyl)-3-methyl- pyrrolidin-3-ol

LCMS found 614.1 205 (R)-1-(3-Chloro-4-(4- (2-(1-(methylsulfonyl)-piperidin-4-yl)amino)- 5-(trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)- pyrrolidin-3-ol

LCMS found 600.2 206 (S)-1-(3 -Chloro-4- (4-(2-((1-(methyl-sulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)-pyrimidin-4-yl)-1H- imidazol-1-yl)benzyl)- pyrrolidin-3-ol

LCMS found 600.2 207 (R)-4-(1-(2-Chloro-4- ((3-methoxypyrrolidin-1-yl)methyl)phenyl)- 1H-imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS found 614.2 208 4-(1-(2-Chloro-4- (piperidin-1-ylmethyl)-phenyl)-1H-imidazol- 4-yl)-N-(1-(methyl- sulfonyl)piperidin-4-yl-5-(trifluoro- methyl)pyrimidin-2- amine

LCMS found 598.4 209 4-(1-(2-Chloro-4-((4- methylpiperazin-1-yl)methyl)phenyl)- 1H-imidazol-4-yl)-N- (1-(methylsulfonyl)-piperidin-4-yl)-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS found 613.4 210 4-(1-(2-Chloro-4- (morpholinomethyl)-phenyl)-1H-imidazol- 4-yl)-N-(1-(methyl- sulfonyl)piperidin-4-yl)-5-(trifluoro- methyl)pyrimidin-2- amine

LCMS found 600.3 211 4-(3-Chloro-4-(4-(2- ((1-(methylsulfonyl)-piperidin-4-yl)amino)- 5-(trifluoromethyl)- pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)- 1-methylpiperazin-2- one

LCMS found 627.2 212 4-(1-(2-Chloro-4- ((hexahydropyrrolo-[1,2-a]pyrazin-2(1H)- yl)methyl)phenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)- piperidin-4-yl)-5- (trifluoromethyl)-pyrimidin-2-amine

LCMS found 639.2 213 4-(1-(4-((2-Oxa-5- azabicyclo[2.2.1]-heptan-5-yl)methyl)- 2-chlorophenyl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)- piperidin-4-yl-5- (trifluoromethyl)- pyrimidin-2-amine

LCMS found 612.2 214 4-(1-(4-((3-Oxa-6- azabicyclo[3.1.1]-heptan-6-yl)methyl)- 2-chlorophenyl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)- piperidin-4-yl)-5- (trifluoromethyl)-pyrimidin-2-amine

LCMS found 612.2 215 4-(1-(4-((3-Oxa-8- azabicyclo[3.2.1]-octan-8-yl)methyl)- 2-chlorophenyl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)- piperidin-4-yl)-5- (trifluoromethyl)-pyrimidin-2-amine

LCMS found 626.2 216 4-(1-(4-((2-Oxa-5- azabicyclo[2.2.2]-octan-5-yl)methyl)-2- chlorophenyl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)- piperidin-4-yl)-5- (trifluoromethyl)-pyrimidin-2-amine

LCMS found 626.1 217 2-((3-Chloro-4-(4-(2- (((3R,4S)-3-methyl-1-(methylsulfonyl)- piperidin-4-yl)amino)- 5-(trifluoromethyl)-pyrimidin-4-yl)-1H- imidazol-1-yl)benzyl)- amino)acetonitrile

LCMS found 583.2 218 4-(1-(2-Chloro-4- ((ethylamino)methyl)-phenyl)-1H-imidazol- 4-yl)-N-((3R,4S)-3- methyl-1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)-pyrimidin- 2-amine

LCMS found 572.2 219 4-(1-(4-(Azetidin-1- ylmethyl)-2-chloro-phenyl)-1H-imidazol- 4-yl)-N-((3R,4S)-3- methyl-1-(methyl-sulfonyl)piperidin- 4-yl)-5-(trifluoro- methyl)pyrimidin-2- amine

LCMS found 584.2 220 4-(1-(2-Chloro-4- ((dimethylamino)-methyl)phenyl)-1H- imidazol-4-yl)-N- ((3R,4S)-3-methyl-1-(methylsulfonyl)- piperidin-4-yl)-5- (trifluoromethyl)-pyrimidin-2-amine

LCMS found 572.2 221 4-(1-(2-Chloro-4- ((cyclopropylamino)-methyl)phenyl)-1H- imidazol-4-yl)-N- ((3R,4S)-1-(cyclo-propylsulfonyl)-3- methylpiperidin-4- yl)-5-(trifluoro-methyl)pyrimidin- 2-amine

LCMS found 610.2 222 4-(1-(2-Chloro-4- ((dimethylamino)-methyl)phenyl)-1H- imidazol-4-yl)-N- ((3R,4S)-1-(cyclo-propylsulfonyl)-3- methylpiperidin-4- yl)-5-(trifluoro-methyl)pyrimidin-2- amine

LCMS found 598.2 223 4-(1-(2-Chloro-4- ((methylamino)-methyl)phenyl)-1H- imidazol-4-yl)-N- ((3R,4S)-1-(cyclo-propylsulfonyl)-3- methylpiperidin-4- yl)-5-(trifluoro-methyl)pyrimidin-2- amine

LCMS found 584.1 224 4-(1-(2-Chloro-4-((3- methylazetidin-1-yl)methyl)phenyl)- 1H-imidazol-4-yl)-N- ((3R,4S)-3-fluoro-1-(methylsulfonyl)- piperidin-4-yl)-5- (trifluoromethyl)-pyrimidin-2-amine

LCMS found 602.1 225 4-(1-(2-Chloro-4- ((methylamino)-methyl)phenyl)-1H- imidazol-4-yl)-N- ((3R,4R)-3-fluoro-1-(methylsulfonyl)- piperidin-4-yl)-5- (trifluoromethyl)-pyrimidin-2-amine

LCMS found 562.2 226 4-(1-(2-Chloro-4- ((methylamino)-methyl)phenyl)-1H- imidazol-4-yl)-2-((1-(methylsulfonyl)-piperidin-4-yl)- amino)pyrimidine- 5-carbonitrile

LCMS found 501.2 227 5-Chloro-4-(1-(2- chloro-4-((methyl- amino)methyl)-phenyl)-1H-imidazol- 4-yl)-N-(1-(methyl- sulfonyl)piperidin-4-yl)pyrimidin-2-amine

LCMS found 510.2

Example 228.4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1: tert-Butyl4-((4-(1-(2-chloro-4-formylphenyl)-H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

A mixture of tert-butyl4-((4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate(113 mg, 0.274 mmol), 3-chloro-4-fluorobenzaldehyde (217 mg, 1.37 mmol),cesium carbonate (890 mg, 2.74 mmol), and MeCN (10 mL) was sparged withnitrogen. The reaction mixture was heated at 80° C. for 30 minutes.After filtration of the resultant mixture at room temperature, thefiltrate was purified by flash column chromatography (Agela Flash ColumnSilica-CS (40 g), eluting with a gradient of 0 to 10% CH₂Cl₂/methanol)to afford the desired product, which was used in the next reactionwithout further purification. LCMS calculated for C₂₅H₂₇ClF₃N₆₀₃ (M+H)⁺:m/z=551.2; Found 551.2.

Step 2: tert-Butyl4-((4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

In a vial with a stir bar, a mixture of tert-butyl4-((4-(1-(2-chloro-4-formylphenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate,azetidine hydrochloride (256 mg, 2.74 mmol), triethylamine (0.57 mL, 4.1mmol), acetic acid (0.40 mL, 7.0 mmol), THE (5 mL), and MeOH (5 mL) wasstirred at 70° C. for 1 hour. NaBH₃CN (200 mg, 3.2 mmol) was added tothe resultant solution at room temperature. The mixture was heated at60° C. for 30 minutes and the solution was then concentrated in vacuo.The residue was dissolved in MeOH and purified by prep-LCMS (XBridgecolumn, eluting with a gradient of acetonitrile/water containing 0.1%NH₄OH, at flow rate of 60 mL/min) to afford the desired product, whichwas used in the next reaction without further purification. LCMScalculated for C₂₈H₃₄ClF₃N₇O₂ (M+H)⁺: m/z=592.2; Found 592.4.

Step 3:4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-H-imidazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

The tert-butyl4-((4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylatewas treated with TFA (5 mL) at room temperature for 2 days. Theresultant solution was concentrated under reduced pressure to afford thedesired product, which was used in the next reaction without furtherpurification. LCMS calculated for C₂₃H₂₆ClF₃N₇ (M+H)⁺: m/z=492.2; Found492.2.

Step 4:4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-H-imidazol-4-yl)-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with stir bar, a solution of4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine,triethylamine (0.10 mL, 0.72 mmol) was dissolved in DCM (1 mL).Cyclopropanesulfonyl chloride (14.3 mg, 0.102 mmol) was added intoreaction mixture. After stirring at room temperature for 1 hour, themixture was quenched by saturated aqueous NaHCO₃ solution, and themixture was then concentrated under reduced pressure. The materialobtained was dissolved in MeOH and purified by prep-LCMS (Sunfire C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/in). LCMS calculated for C₂₆H₃₀ClF₃N₇O₂S(M+H)⁺: m/z=596.2; Found 596.1.

Example 229.4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(ethylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 228, using ethanesulfonyl chloride instead ofcyclopropanesulfonyl chloride as starting material for Step 4. LCMScalculated for C₂₅H₃₀ClF₃N₇O₂S (M+H)⁺: m/z=584.2; Found 584.2.

Example 230.4-((4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-cyclopropylpiperidine-1-sulfonamide

This compound was prepared according to the procedures described inExample 228, using cyclopropylsulfamoyl chloride instead ofcyclopropanesulfonyl chloride as starting material for Step 4. LCMScalculated for C₂₆H₃₁ClF₃N₈O₂S (M+H)⁺: m/z=611.2; Found 611.2.

Example 231.(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)methanol

A mixture of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(100 mg, 0.256 mmol), 3-chloro-4-fluorobenzaldehyde (122 mg, 0.768mmol), cesium carbonate (584 mg, 1.79 mmol) and acetonitrile (3 mL) wassparged with nitrogen. The reaction mixture was heated at 80° C. for 30minutes. After filtration of the resultant mixture, the filtrate wasconcentrated. The residue was dissolved in MeOH (3 mL), followed by theaddition of sodium borohydride (48.5 mg, 1.28 mmol). After stirring atroom temperature for 2 hours, the solution was concentrated underreduced pressure. The residue was dissolved in MeOH and purified byprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₁H₂₃ClF₃N₆O₃S (M+H)⁺:m/z=531.1; Found 531.2.

Example 232.2-(Hydroxymethyl)-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

A mixture of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(20 mg, 0.051 mmol), methyl 2-cyano-6-fluorobenzoate (45.9 mg, 0.256mmol), cesium carbonate (167 mg, 0.512 mmol) and acetonitrile (3 mL) wassparged with nitrogen. The reaction mixture was heated at 80° C. for 1hour. After filtration of the resultant mixture, the filtrate wasconcentrated. The residue was dissolved in MeOH (3 mL), followed by theaddition of sodium borohydride (19.4 mg, 0.512 mmol). After stirring atroom temperature for 2 hours, the solution was concentrated underreduced pressure. The residue was dissolved in MeOH and purified byprep-LCMS (XBridge column, eluting with a gradient of acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min) to afford the desiredproduct. LCMS calculated for C₂₂H₂₃F₃N₇O₃S (M+H)⁺: m/z=522.2; Found522.2.

Example 233.4-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)isobenzofuran-1(3H)-one

In a vial with stir bar,2-(hydroxymethyl)-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile(10 mg, 0.019 mmol) was dissolved in TFA (3 mL), and stirred at roomtemperature for 12 hours. The solution was quenched by water, and theresultant solution was concentrated under reduced pressure. The residuewas dissolved in MeOH and purified by prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min) to afford the desired product. LCMS calculatedfor C₂₂H₂₂F₃N₆O₄S (M+H)⁺: m/z=523.1; Found 523.1.

TABLE 21 The compounds in Table 21 were prepared in accordance with thesynthetic protocols set forth in Example 231 using the appropriatestarting materials. Analytical Ex. Name Structure data 234(3-Chloro-4-(4-(2-(((3R,4S)-3- methyl-1- (methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1-yl)phenyl)methanol

LCMS found 545.1 235 3-(Hydroxymethyl)-4-(4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1- yl)benzonitrile

LCMS found 522.1 236 6-(Hydroxymethyl)-5-(4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1- yl)picolinonitrile

LCMS found 523.1 237 (2-(4-(2-((1- (Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1-yl)phenyl)methanol

LCMS found 497.1

Example 238.4-(1-(4-((H-Imidazol-1-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with stir bar, to a solution of N,N-diisopropyl ethylamine (68μL, 0.39 mmol),(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)methanol(Example 231, 68.6 mg, 0.129 mmol) in DCM (5 mL) was addedmethanesulfonyl chloride (10 μL, 0.13 mmol). After the reaction mixturewas stirred at room temperature for 1 hour, the mixture was concentratedunder reduced pressure. The residue was mixed with imidazole (18 mg,0.26 mmol) and DMF (1 mL), and the solution was then heated at 100° C.for 2 hours. The resultant solution was diluted in MeOH and purified byprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₄H₂₅ClF₃N₈O₂S (M+H)⁺:m/z=581.1; Found 581.1.

TABLE 22 The compounds in Table 22 were prepared in accordance with thesynthetic protocols set forth in Example 238 using the appropriatestarting materials. Analytical Ex. Name Structure data 2394-(1-(4-((4H-1,2,4-Triazol-4- yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 582.1 240 4-(1-(4-((1H-1,2,4-Triazol-1-yl)methyl)-2-chlorophenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 582.1 241 4-(1-(4-((2H-1,2,3-Triazol-2-yl)methyl)-2-chlorophenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 582.3 242 4-(1-(4-((1H-1,2,3-Triazol-1-yl)methyl)-2-chlorophenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 582.2 243 4-(1-(4-((2H-Tetrazol-2-yl)methyl)-2-chlorophenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 583.1 244 4-(1-(4-((1H-Tetrazol-1-yl)methyl)-2-chlorophenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 583.1

Example 245.4-(1-(2-(Difluoromethyl)-6-((methylamino)methyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1: Methyl 6-(difluoromethyl)-5-fluoropicolinate

In a vial with stir bar, (trimethylsilyl)diazomethane (2.0 M in hexanes,0.45 mL, 0.90 mmol) was added dropwise to a solution of6-(difluoromethyl)-5-fluoropicolinic acid (115 mg, 0.602 mmol) in MeOH(10 mL). The reaction mixture was stirred at room temperature for 1hour. The mixture was quenched with AcOH and concentrated in vacuo toafford the desired product, which was used in the next reaction withoutfurther purification. LCMS calculated for C₈H₇F₃NO₂ (M+H)⁺: m/z=206.0;Found 206.2.

Step 2:(6-(Difluoromethyl)-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)pyridin-2-yl)methanol

A mixture of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2, 37.8 mg, 0.0970 mmol), methyl6-(difluoromethyl)-5-fluoropicolinate (59.6 mg, 0.290 mmol), cesiumcarbonate (189 mg, 0.581 mmol) and acetonitrile (5 mL) was sparged withnitrogen. The reaction mixture was heated at 80° C. for 30 minutes.After filtration of the resultant mixture, the filtrate wasconcentrated. The residue was dissolved in MeOH (3 mL), followed by theaddition of sodium borohydride (48.5 mg, 1.28 mmol). After stirring atroom temperature for 2 hours, the solution was purified by prep-LCMS(XBridge column, eluting with a gradient of acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min) to afford the desiredproduct. LCMS calculated for C₂₁H₂₃F₅N₇O₃S (M+H)⁺: m/z=548.1; Found548.3.

Step 3:4-(1-(2-(Difluoromethyl)-6-((methylamino)methyl)pyridin-3-yl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a microwave vial with a stir bar, to a solution of N,N-diisopropylethylamine (68 μL, 0.39 mmol),(6-(difluoromethyl)-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)pyridin-2-yl)methanol(10.6 mg, 0.019 mmol) in DCM (5 mL) was added methanesulfonyl chloride(6 μL, 0.08 mmol). After the reaction mixture was stirred at roomtemperature for 1 hour, the mixture was concentrated under reducedpressure. The residue was mixed with methylamine (2 M in THF, 0.100 mL,0.200 mmol) and DMF (1 mL), and the solution was then heated at 100° C.for 2 hours. The resultant solution was diluted in MeOH and purified byprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₂H₂₆F₅N₈O₂S (M+H)⁺:m/z=561.2; Found 561.2.

Example 246.4-(1-(6-((Dimethylamino)methyl)-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:(5-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-(trifluoromethyl)pyridin-2-yl)methanol

This compound was prepared according to the procedures described inExample 245, using 5-fluoro-6-(trifluoromethyl)picolinic acid instead of6-(difluoromethyl)-5-fluoropicolinic acid as starting material for Step1, and methyl 5-fluoro-6-(trifluoromethyl)picolinate instead of methyl6-(difluoromethyl)-5-fluoropicolinate for Step 2. LCMS calculated forC₂₁H₂₂F₆N₇O₃S (M+H)⁺: m/z=566.1; Found 566.2.

Step 2:4-(1-(6-((Dimethylamino)methyl)-2-(trifluoromethyl)pyridin-3-yl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 245, using dimethylamine instead of methylamine as startingmaterial for Step 3. LCMS calculated for C₂₃H₂₇F₆N₈O₂S (M+H)⁺:m/z=593.2; Found 593.2.

Example 247.4-(1-(6-(Azetidin-1-ylmethyl)-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 246, using azetidine instead of dimethylamine as startingmaterial for Step 2. LCMS calculated for C₂₄H₂₇F₆N₈O₂S (M+H)⁺:m/z=605.2; Found 605.1.

Example 248.1-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethan-1-ol

In a vial with stir bar, to a solution of3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde(Step 1 in Example 3, 10 mg, 0.019 mmol) in THE (2 mL) was addedmethylmagnesium bromide (1.0 M in dibutyl ether, 0.10 mL, 0.10 mmol).After stirring at room temperature for 1 hour, the mixture was filteredand then the filtrate was concentrated under reduced pressure. Theresidue was dissolved in MeOH and purified by prep-LCMS (Sunfire C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min) to afford the desired product. LCMScalculated for C₂₂H₂₅ClF₃N₆O₃S (M+H)⁺: m/z=545.1; Found 545.2.

Example 249.5-((Methylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 3, using 2-fluoro-5-formylbenzonitrile instead of3-chloro-4-fluorobenzaldehyde as starting material. LCMS calculated forC₂₃H₂₆F₃N₈O₂S (M+H)⁺: m/z=535.2; Found 535.2.

Example 250.4-(1-(4-((Dimethylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:4-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzaldehyde

In a vial with a stir bar, a mixture of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(280 mg, 0.717 mmol), 4-fluoro-3-(trifluoromethyl)benzaldehyde (490 μL,3.6 mmol), cesium carbonate (2.3 g, 7.2 mmol), and acetonitrile (10 mL)was sparged with N₂, and the mixture was stirred at 70° C. for 30minutes. After filtration of the resultant mixture at room temperature,the filtrate was purified by flash column chromatography (Agela FlashColumn Silica-CS (40 g), eluting with a gradient of 0 to 10%CH₂Cl₂/methanol) to afford the desired product. LCMS calculated forC₂₂H₂₁F₆N₆O₃S (M+H)⁺: m/z=563.1; Found 563.1.

Step 2:4-(1-(4-((Dimethylamino)methyl)-2-(trifluoromethyl)phenyl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, a mixture of3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde,dimethylamine (2 M in THF, 3.0 mL, 6.0 mmol), triethylamine (0.10 mL,0.72 mmol), acetic acid (0.5 mL, 8.7 mmol), THE (10 mL), and MeOH (10mL) was stirred at 70° C. for 1 hour. NaBH₃CN (200 mg, 3.2 mmol) wasadded to the resultant solution at room temperature. The mixture washeated at 60° C. for 30 minutes and the solution was then concentratedin vacuo. The residue was dissolved in MeOH and purified by prep-LCMS(XBridge column, eluting with a gradient of acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 m/min). Fractions containingthe desired product were then concentrated, and the material obtainedwas dissolved in acetonitrile and purified by prep-LCMS (Sunfire C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1rotamers) δ 9.96 (brs, 1H), 8.65 (s, 0.5H), 8.60 (s, 0.5H), 8.17 (s,1H), 8.13 (s, 0.5H), 8.03 (s, 1H), 8.00-7.76 (m, 3.5H), 4.48 (s, 2H),4.04-3.90 (m, 1H), 3.60-3.45 (m, 2H), 2.91-2.82 (m, 5H), 2.79 (s, 6H),2.01-1.89 (m, 2H), 1.66-1.50 (m, 2H). LCMS calculated for C₂₄H₂₈F₆N₇O₂S(M+H)⁺: m/z=592.2; Found 592.2.

Example 251.4-(1-(4-(Azetidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, a mixture of4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzaldehyde(Step 1 in Example 250, 60 mg, 0.11 mmol), azetidine hydrochloride (50mg, 0.53 mmol), acetic acid (0.20 mL, 3.5 mmol), triethylamine (0.20 mL,1.4 mmol), MeOH (10 mL), and THE (10 mL) was stirred at 70° C. for 1hour. After the solution was cooled to room temperature, NaCNBH₃ (200mg, 3.2 mmol) was added to the resultant mixture. The solution wasstirred at room temperature for 30 minute, and then 60° C. for 30minutes. The resultant mixture was concentrated under reduced pressure.The residue was dissolved in MeOH and purified by prep-LCMS (Sunfire C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1rotamers) δ 10.54 (s, 1H), 8.65 (s, 0.5H), 8.59 (s, 0.5H), 8.12 (s,1.5H), 8.03 (s, 1H), 8.00-7.76 (m, 3.5H), 4.56 (s, 2H), 4.24-3.91 (m,5H), 3.62-3.43 (m, 2H), 2.95-2.76 (m, 5H), 2.46-2.27 (m, 2H), 2.03-1.88(m, 2H), 1.66-1.51 (m, 2H). LCMS calculated for C₂₅H₂₈F₆N₇O₂S (M+H)⁺:m/z=604.2; Found 604.3.

Example 252.4-(1-(6-(Azetidin-1-ylmethyl)-2-methylpyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures describe inExample 250, using 5-fluoro-6-methylpicolinaldehyde instead of4-fluoro-3-(trifluoromethyl)benzaldehyde as starting material for Step1, and azetidine hydrochloride instead of dimethylamine as startingmaterial for Step 2. LCMS calculated for C₂₄H₃₀F₃N₈O₂S (M+H)⁺:m/z=551.2; Found 551.2.

Example 253.4-(1-(2-Chloro-4-((dimethylamino)methyl)-3-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 250, using 3-chloro-2,4-difluorobenzaldehyde instead of4-fluoro-3-(trifluoromethyl)benzaldehyde as starting material. ¹H NMR(TFA salt, 500 MHz, DMSO-d₆, 1:1 rotamers) δ 10.1 (brs, 1H), 8.66 (s,0.5H), 8.60 (s, 0.5H), 8.22 (s, 0.5H), 8.14 (s, 1H), 8.04 (s, 0.5H),7.98-7.87 (m, 1H), 7.80-7.64 (m, 2H), 4.48 (s, 2H), 4.08-3.91 (m, 1H),3.59-3.47 (m, 2H), 2.94-2.76 (m, 11H), 2.00-1.91 (m, 2H), 1.65-1.53 (m,2H). LCMS calculated for C₂₃H₂₇ClF₄N₇O₂S (M+H)⁺: m/z=576.2; Found 576.3.

TABLE 23 The compounds in Table 23 were prepared in accordance with thesynthetic protocols set forth in Example 250 using the appropriatestarting materials. Ex. Name Structure Analytical data 254 4-(1-(4-((Methylamino)methyl)-2- (trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 578.3 ¹H NMR (TFA salt, 500 MHz, DMSO- d₆, 1:1 rotamers) δ8.96 (brs, 2H), 8.72- 8.54 (m, 1H), 8.18- 8.08 (m, 1.5H), 8.04 (s, 1H),7.98-7.75 (m, 3.5H), 4.41-4.27 (m, 2H), 4.06-3.90 (m, 1H), 3.62-3.43 (m,2H), 2.93-2.76 (m, 5H), 2.68-2.57 (m, 3H), 2.01-1.89 (m, 2H), 1.65-1.52(m, 2H) 255 4-(1-(4- ((Ethylamino)methyl)-2- (trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 592.2 256 4-(1-(4- ((Cyclopropylamino)methyl)- yl)-2-(trifluoromethyl)phenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 604.2 257 4-(1-(4- ((Ethyl(methyl)amino) methyl)-2-(trifluoromethyl)phenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 606.1 258 4-(1-(4- ((Diethylamino)methyl)- 2-(trifluoromethyl)phenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 620.2 259 1-(4-(4-(2-((1- (Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)- 3-(trifluoromethyl)benzyl) azetidin-3-ol

LCMS found 620.2 260 (S)-1-(4-(4-(2-((1- (Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)-(trifluoromethyl)benzyl) pyrrolidin-3-ol

LCMS found 634.1 261 (S)-3-Methyl-1-(4-(4-(2- ((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)- 3- (trifluoromethyl)benzyl) pyrrolidin-3-ol

LCMS found 648.2 262 4-Methyl-1-(4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)- 3-(trifluoromethyl)benzyl) piperidin-4-ol

LCMS found 662.3 263 4-(1-(6- ((Dimethylamino)methyl)-2-methylpyridin-3-yl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 539.2 264 4-(1-(2-Methyl-6-((3- methylazetidin-1-yl)methyl)pyridin-3-yl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 565.2 265 4-(1-(6-((3,3- Dimethylazetidin-1- yl)methyl)-2-methylpyridin-3-yl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 579.3 266 4-(1-(2-Fluoro-4- ((methylamino)methyl)phenyl)-1H-imidazol-4-yl)- N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 528.1 267 4-(1-(4- ((Dimethylamino)methyl)-2-fluorophenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 542.2 268 4-(1-(2-Chloro-3-fluoro-4- ((methylamino)methyl)phenyl)-1H-imidazol-4-yl)- N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 562.2 269 4-(1-(4-(Azetidin-1- ylmethyl)-2-chloro-3-fluorophenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 588.1 270 4-(1-(2-Chloro-3-fluoro-4- ((3-methylazetidin-1-yl)methyl)phenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 602.2

Example 271.4-(1-(4-((Dimethylamino)methyl)-2-methylphenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:3-Methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde

In a vial with a stir bar, a mixture of 4-fluoro-3-methylbenzaldehyde(270 μL, 2.2 mmol),4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2, 170 mg, 0.435 mmol), cesium carbonate (1.4 g, 4.4mmol), and DMF (10 mL) was sparged with nitrogen. The mixture was heatedat 100° C. for 1 hour. After cooling to room temperature, the resultantmixture was filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography (Agela Flash ColumnSilica-CS (40 g), eluting with a gradient of 0 to 10% CH₂Cl₂/methanol)to afford the desired product. LCMS calculated for C₂₂H₂₄F₃N₆O₃S (M+H)⁺:m/z=509.2; Found 509.2.

Step 2:4-(1-(4-((Dimethylamino)methyl)-2-methylphenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, a mixture of3-methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde(110 mg, 0.216 mmol), dimethylamine (2 M in THF, 2.0 mL, 4.0 mmol),acetic acid (0.30 mL, 5.2 mmol), triethylamine (0.30 mL, 2.2 mmol), MeOH(5 mL), and THE (5 mL) was stirred at 70° C. for 1 hour. After thesolution was cooled to room temperature, NaCNBH₃ (200 mg, 3.2 mmol) wasadded to the resultant mixture. The solution was stirred at roomtemperature for 30 minutes, and then 60° C. for 30 minutes. Theresultant mixture was concentrated under reduced pressure. The residuewas dissolved in MeOH and purified by prep-LCMS (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 4:6rotamers) δ 9.83 (brs, 1H), 8.65 (s, 0.4H), 8.59 (s, 0.6H), 8.15 (s,0.6H), 8.04 (s, 1H), 7.95-7.82 (m, 1.4H), 7.61-7.45 (m, 3H), 4.38-4.27(m, 2H), 4.11-3.92 (m, 1H), 3.60-3.45 (m, 2H), 2.94-2.81 (m, 5H),2.81-2.66 (m, 6H), 2.24 (s, 3H), 2.02-1.89 (m, 2H), 1.65-1.51 (m, 2H).LCMS calculated for C₂₄H₃₁F₃N₇O₂S (M+H)⁺: m/z=538.2; Found 538.3.

Example 272.4-(1-(2-Methyl-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 271, using methanamine instead of dimethylamine as startingmaterial. LCMS calculated for C₂₃H₂₉F₃N₇O₂S (M+H)⁺: m/z=524.2; Found524.2.

Example 273.4-(1-(2-Chloro-4-(1-(ethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:1-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethan-1-one

This compound was prepared according to the procedures described inExample 250, using 1-(3-chloro-4-fluorophenyl)ethan-1-one instead of4-fluoro-3-(trifluoromethyl)benzaldehyde as starting material forStep 1. LCMS calculated for C₂₂H₂₃ClF₃N₆O₃S (M+H)⁺: m/z=543.1; Found543.1.

Step 2:4-(1-(2-Chloro-4-(1-(ethylamino)ethyl)phenyl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, a mixture of1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethan-1-one(250 mg, 0.46 mmol), ethylamine (2 M in THF, 1.0 mL, 2.0 mmol), aceticacid (0.20 mL, 3.5 mmol), triethylamine (0.20 mL, 1.4 mmol), MeOH (5mL), and THE (5 mL) was stirred at 70° C. for 1 hour. After the solutionwas cooled to room temperature, NaCNBH₃ (200 mg, 3.2 mmol) was added tothe resultant mixture. The solution was stirred at room temperature for30 minutes, and then 60° C. for 30 minutes. The resultant mixture wasconcentrated under reduced pressure. The residue was dissolved in MeOHand purified by prep-LCMS (Sunfire C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 4:6 rotamers) δ 9.09 (brs, 1H), 8.94(brs, 1H), 8.65 (s, 0.4H), 8.59 (s, 0.6H), 8.20 (s, 0.6H), 8.09 (s, 1H),7.99 (s, 0.4H), 7.95-7.85 (m, 2H), 7.84-7.74 (m, 1H), 7.67 (d, J=8.2 Hz,1H), 4.58-4.47 (m, 1H), 4.08-3.93 (m, 1H), 3.59-3.47 (m, 2H), 3.01-2.70(m, 7H), 2.01-1.90 (m, 2H), 1.65-1.52 (m, 5H), 1.18 (t, J=7.2 Hz, 3H).LCMS calculated for C₂₄H₃₀ClF₃N₇O₂S (M+H)⁺: m/z=572.2; Found 572.3.

Example 274.4-(1-(4-(1-(Azetidin-1-yl)ethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 273, using azetidine hydrochloride instead of ethylamine asstarting material. LCMS calculated for C₂₅H₃₀ClF₃N₇O₂S (M+H)⁺:m/z=584.2; Found 584.1.

Example 275.4-(1-(2-Chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:4-(1-(2-Chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 273, using methanamine instead of ethylamine as startingmaterial. LCMS calculated for C₂₃H₂₈ClF₃N₇O₂S (M+H)⁺: m/z=558.2; Found558.2.

Step 2:tert-Butyl(1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-H-imidazol-1-yl)phenyl)ethyl)(methyl)carbamate

In a vial with a stir bar, a mixture of4-(1-(2-chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(12.8 mg, 0.023 mmol), triethylamine (14 μL, 0.10 mmol), di-tert-butyldicarbonate (11 mg, 0.051 mmol), and DCM (3 mL) was stirred at roomtemperature for 4 hours. After concentration of the resultant mixture,the residue was purified by flash column chromatography (Agela FlashColumn Silica-CS (24 g), eluting with a gradient of 0 to 10%CH₂Cl₂/methanol) to afford the desired product. Then, the twoenantiomers were separated with chiral prep-HPLC (Phenomenex LuxCellulose-1, 21.2×250 mm, 5 micron, eluting with 45% EtOH in hexanes, atflow rate of 20 mL/min, t_(R, peak 1)=6.9 min, t_(R, peak 2)=10.7 min).Peak 1: LCMS calculated for C₂₈H₃₆ClF₃N₇O₄S (M+H)⁺: m/z=658.2; Found658.4. Peak 2: LCMS calculated for C₂₈H₃₆ClF₃N₇O₄S (M+H)⁺: m/z=658.2;Found 658.4.

Step 3:4-(1-(2-Chloro-4-(1-(methylamino)ethyl)phenyl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, tert-butyl(1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethyl)(methyl)carbamate(Peak 1, 7.0 mg, 10 μmol) was dissolved in TFA (3 mL), and stirred atroom temperature for 3 hours. After the resultant mixture wasconcentrated under reduced pressure, the residue was dissolved in MeOH.The solution was purified by prep-LCMS (Sunfire C18 column, eluting witha gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₃H₂₈ClF₃N₇O₂S (M+H)⁺: m/z=558.2; Found558.2.

Example 276.4-(1-(2-Chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, tert-butyl(1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethyl)(methyl)carbamate(Example 275 in Step 2, Peak 2, 7.0 mg, 10 μmol) was dissolved in TFA (3mL), and stirred at room temperature for 3 hours. After the resultantmixture was concentrated under reduced pressure, the residue wasdissolved in MeOH. The solution was purified by prep-LCMS (Sunfire C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₂₃H₂₈ClF₃N₇O₂S(M+H)⁺: m/z=558.2; Found 558.1.

Example 277.4-(1-(2-Chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1: tert-Butyl6-(3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate

In a microwave vial with a stir bar, a mixture of4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 42, 51 mg, 0.080 mmol), tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate(73.8 mg, 0.239 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (65.0 mg, 0.080 mmol), sodiumcarbonate (25.3 mg, 0.239 mmol), acetonitrile (3 mL), and water (0.6 mL)was sparged with nitrogen and heated at 80° C. for 10 hours. Aftercooling to room temperature, the solution was filtered through a pad ofSiliaMetS Thiol®, and concentrated. The residue was purified by flashcolumn chromatography (Agela Flash Column Silica-CS (24 g), eluting witha gradient of 0 to 20% CH₂Cl₂/methanol) to afford the desired product,which was used in the next reaction without further purification. LCMScalculated for C₃₁H₃₈ClF₃N₇O₄S (M+H)⁺: m/z=696.2; Found 696.3.

Step 2:4-(1-(2-Chloro-4-(piperidin-2-yl)phenyl)-H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, tert-butyl6-(3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylatewas dissolved in TFA (3 mL), and stirred at room temperature for 2hours. The mixture was concentrated in vacuo and then dissolved in THF(5 mL). To this solution was added triethylamine (300 μL, 2.15 mmol) andacetic acid (100 μL, 1.75 mmol), followed by sodiumtriacetoxyborohydride (84 mg, 0.40 mmol). The mixture was stirred atroom temperature for 16 hours. The resultant solution was quenched bysaturated aqueous NaHCO₃ solution, and the mixture was then concentratedunder reduced pressure. The material obtained was dissolved in MeOH andpurified by prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/in) toafford the desired product, which was used in the next reaction withoutfurther purification. LCMS calculated for C₂₆H₃₂ClF₃N₇O₂S (M+H)⁺:m/z=598.2; Found 598.2.

Step 3: tert-Butyl2-(3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)piperidine-1-carboxylate

This compound was prepared according to the procedures described inExample 275, using4-(1-(2-chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineinstead of4-(1-(2-chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material for Step 2. Separation conditions of chiralprep-HPLC (Phenomenex Lux Cellulose-1, 21.2×250 mm, 5 micron, elutingwith 30% EtOH in hexanes, at flow rate of 20 mL/min, t_(R, peak 1)=7.7min, t_(R, peak 2)=10.2 min). Peak 1: LCMS calculated forC₃₁H₄₀ClF₃N₇O₄S (M+H)⁺: m/z=698.2; Found 698.2; Found 698.2. Peak 2:LCMS calculated for C₃₁H₄₀ClF₃N₇O₄S (M+H)⁺: m/z=698.2; Found 698.2.

Step 4:4-(1-(2-Chloro-4-(piperidin-2-yl)phenyl)-H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 275, using tert-butyl2-(3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)piperidine-1-carboxylate(Example 277 in Step 3, Peak 1) instead of tert-butyl(1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethyl)(methyl)carbamateas starting material for Step 3. LCMS calculated for C₂₆H₃₂ClF₃N₇O₂S(M+H)⁺: m/z=598.2; Found 598.2.

Example 278.4-(1-(2-Chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 276, using tert-butyl2-(3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)piperidine-1-carboxylate(Example 277 in Step 3, Peak 2) instead of tert-butyl(1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethyl)(methyl)carbamateas starting material. LCMS calculated for C₂₆H₃₂ClF₃N₇O₂S (M+H)⁺:m/z=598.2; Found 598.2.

Example 279.4-(1-(4-((Dimethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde

In a vial with a stir bar, a mixture of4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 38, 200 mg, 0.50 mmol), 3,4-difluorobenzaldehyde (0.27 mL,2.5 mmol), cesium carbonate (1.6 g, 5.0 mmol), and MeCN (10 mL) wassparged with N₂, and the mixture was stirred at room temperature for 5hours. After filtration of the resultant mixture, the filtrate waspurified by flash column chromatography (Agela Flash Column Silica-CS(40 g), eluting with a gradient of 0 to 10% CH₂Cl₂/methanol) to affordthe desired product. LCMS calculated for C₂₂H₂₃F₄N₆O₃S (M+H)⁺:m/z=527.1; Found 527.3.

Step 2:4-(1-(4-((Dimethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, a mixture of3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde(0.23 g, 0.44 mmol), dimethylamine (2 M in THF, 2.0 mL, 4.0 mmol),triethylamine (0.20 mL, 1.4 mmol), acetic acid (0.20 mL, 3.5 mmol), THE(10 mL), and MeOH (10 mL) was stirred at 70° C. for 1 hour. NaBH₃CN (200mg, 3.2 mmol) was added to the resultant solution at room temperature.The mixture was heated at 60° C. for 30 minutes and the solution wasthen concentrated in vacuo. The residue was dissolved in MeOH andpurified by prep-LCMS (XBridge column, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 m/min).Fractions containing the desired product were then concentrated, and thematerial obtained was dissolved in acetonitrile and purified byprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 m/min). ¹HNMR (TFA salt, 500 MHz, DMSO-d₆, 1:1 rotamers) δ 9.95 (brs, 1H), 8.63(s, 0.5H), 8.58 (s, 0.5H), 8.01 (s, 0.5H), 7.95-7.85 (m, 1H), 7.85-7.73(m, 1.5H), 7.69 (d, J=10.5 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 4.39 (s,2H), 4.08-3.91 (m, 1H), 3.59-3.43 (m, 2H), 2.95-2.82 (m, 5H), 2.79 (s,6H), 2.27 (s, 3H), 2.00-1.88 (m, 2H), 1.64-1.51 (m, 2H). LCMS calculatedfor C₂₄H₃₀F₄N₇O₂S (M+H)⁺: m/z=556.2; Found 556.2.

Example 280.4-(1-(4-((Bis(methyl-d)amino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 279, using dimethyl-d₆-amine hydrochloride instead ofdimethylamine (2 M in THF) as starting material. ¹H NMR (TFA salt, 500MHz, DMSO-d₆, 1:1 rotamers) δ 9.82 (brs, 1H), 8.63 (s, 0.5H), 8.57 (s,0.5H), 8.02 (s, 0.5H), 7.93-7.86 (m, 1H), 7.85-7.75 (m, 1.5H), 7.69 (d,J=10.7 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H), 4.38 (s, 2H), 4.07-3.90 (m, 1H),3.59-3.44 (m, 2H), 2.94-2.79 (m, 5H), 2.26 (s, 3H), 2.01-1.89 (m, 2H),1.64-1.52 (m, 2H). LCMS calculated for C₂₄H₂₄D₆F₄N₇O₂S (M+H)⁺:m/z=562.2; Found 562.3.

Example 281.4-(1-(4-(Azetidin-1-ylmethyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 279, using azetidine hydrochloride instead of dimethylamine (2 Min THF) as starting material. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1rotamers) δ 10.4 (brs, 1H), 8.63 (s, 0.5H), 8.57 (s, 0.5H), 8.03 (s,0.5H), 7.95-7.87 (m, 1H), 7.85-7.72 (m, 1.5H), 7.65 (d, J=10.7 Hz, 1H),7.49 (d, J=8.0 Hz, 1H), 4.48 (s, 2H), 4.19-3.91 (m, 5H), 3.58-3.46 (m,2H), 2.93-2.80 (m, 5H), 2.46-2.29 (m, 2H), 2.25 (s, 3H), 1.99-1.89 (m,2H), 1.63-1.53 (m, 2H). LCMS calculated for C₂₅H₃₀F₄N₇O₂S (M+H)⁺:m/z=568.2; Found 568.3.

Example 282.2-(1-(3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-yl)propan-2-ol

This compound was prepared according to the procedures described inExample 279, using 2-(azetidin-3-yl)propan-2-ol hydrochloride instead ofdimethylamine as starting material. LCMS calculated for C₂₈H₃₆F₄N₇O₃S(M+H)⁺: m/z=626.3; Found 626.3.

Example 283.4-(1-(2-Fluoro-4-((3-methylazetidin-1-yl)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 279, using 3-methylazetidine hydrochloride instead ofdimethylamine as starting material. LCMS calculated for C₂₆H₃₂F₄N₇O₂S(M+H)⁺: m/z=582.2; Found 582.2.

Example 284.4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:3-Chloro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde

In a vial with a stir bar, a mixture of4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 38, 70 mg, 0.17 mmol), 3-chloro-4-fluorobenzaldehyde (140mg, 0.87 mmol), cesium carbonate (560 mg, 1.7 mmol), and acetonitrile (3mL) was sparged with N₂, and the mixture was stirred at 70° C. for 30minutes. After filtration of the resultant mixture, the filtrate waspurified by flash column chromatography (Agela Flash Column Silica-CS(40 g), eluting with a gradient of 0 to 10% CH₂Cl₂/methanol) to affordthe desired product. LCMS calculated for C₂₂H₂₃ClF₃N₆O₃S (M+H)⁺:m/z=543.1; Found 543.3.

Step 2:4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

In a vial with a stir bar, a mixture of3-chloro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehyde(80 mg, 0.15 mmol), azetidine hydrochloride (160 mg, 1.7 mmol),triethylamine (0.40 mL, 2.9 mmol), acetic acid (0.40 mL, 7.0 mmol), THF(3 mL), and MeOH (3 mL) was stirred at 70° C. for 1 hour. NaBH₃CN (200mg, 3.2 mmol) was added to the resultant solution at room temperature.The mixture was heated at 60° C. for 30 minutes and the solution wasthen concentrated in vacuo. The residue was dissolved in MeOH andpurified by prep-LCMS (XBridge column, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 m/min).Fractions containing the desired product were then concentrated, and thematerial obtained was dissolved in acetonitrile and purified byprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 m/min). ¹HNMR (TFA salt, 600 MHz, DMSO-d₆, 1:1 rotamers) δ 10.4 (s, 1H), 8.63 (s,0.5H), 8.57 (s, 0.5H), 8.00 (s, 0.5H), 7.94-7.85 (m, 2H), 7.83-7.71 (m,1.5H), 7.63 (d, J=7.0 Hz, 1H), 4.47 (s, 2H), 4.20-3.91 (m, 5H),3.58-3.45 (m, 2H), 2.93-2.81 (m, 5H), 2.46-2.29 (m, 2H), 2.16 (s, 3H),2.01-1.88 (m, 2H), 1.63-1.51 (m, 2H). LCMS calculated forC₂₅H₃₀ClF₃N₇O₂S (M+H)⁺: m/z=584.2; Found 584.3.

Example 285.4-(1-(4-(Azetidin-1-ylmethyl)-2-methylphenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 271, using4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 38) and azetidine hydrochloride instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2) and dimethylamine as starting material. LCMS calculatedfor C₂₆H₃₃F₃N₇O₂S (M+H)⁺: m/z=564.2; Found 564.3.

Example 286.4-(1-(4-((Dimethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 279, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 39) instead of4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 38) as starting material. LCMS calculated forC₂₄H₂₉F₅N₇O₂S (M+H)⁺: m/z=574.2; Found 574.2.

Example 287.N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4-((methylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 279, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 39) and methanamine instead of4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 38) and dimethylamine as starting material. LCMScalculated for C₂₃H₂₇F₅N₇O₂S (M+H)⁺: m/z=560.2; Found 560.1.

Example 288.4-(1-(2-Chloro-4-((dimethylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

Step 1:4-(1-(2-Chloro-4-formylphenyl)-2-methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

In a vial with a stir bar, a mixture of4-(2-methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(60.0 mg, 0.166 mmol), 3-chloro-4-fluorobenzaldehyde (132 mg, 0.830mmol), cesium carbonate (540 mg, 1.66 mmol), and MeCN (3 mL) was spargedwith N₂, and the mixture was stirred at 70° C. for 30 minutes. Afterfiltration of the resultant solution, the filtrate was purified by flashcolumn chromatography (Agela Flash Column Silica-CS (40 g), eluting witha gradient of 0 to 10% CH₂Cl₂/methanol) to afford the desired product.LCMS calculated for C₂₂H₂₃ClN₇O₃S (M+H)⁺: m/z=500.1; Found 500.3.

Step 2:4-(1-(2-Chloro-4-((dimethylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

In a vial with a stir bar, a mixture of4-(1-(2-chloro-4-formylphenyl)-2-methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(20 mg, 0.040 mmol), dimethylamine (2 M in THF, 0.42 mL, 0.84 mmol),triethylamine (0.10 mL, 0.72 mmol), acetic acid (0.10 mL, 1.7 mmol), THE(1 mL), and MeOH (2 mL) was stirred at 70° C. for 1 hour. NaBH₃CN (200mg, 3.2 mmol) was added to the resultant solution at room temperature.The mixture was heated at 60° C. for 30 minutes and the solution wasthen concentrated under reduced pressure. The residue was dissolved inMeOH and purified by prep-LCMS (Sunfire C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to afford the desired product. LCMS calculated for C₂₄H₃₀ClN₈O₂S(M+H)⁺: m/z=529.2; Found 529.2.

Example 289.4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

This compound was prepared according to the procedures described inExample 288, using methanamine instead of dimethylamine as startingmaterial for Step 2. LCMS calculated for C₂₃H₂₈ClN₈O₂S (M+H)⁺:m/z=515.2; Found 515.1.

Example 290.4-(1-(4-Cyano-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile

In a vial with a stir bar, a mixture of4-(2-methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile(10 mg, 0.028 mmol), 3,4-difluorobenzonitrile (19.2 mg, 0.138 mmol),cesium carbonate (90 mg, 0.277 mmol), and acetonitrile (3 mL) wassparged with N₂. After the mixture was stirred at 70° C. for 1 hour, thereaction mixture was filtered. The filtrate was then purified byprep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₂H₂₂FN₈O₂S (M+H)⁺:m/z=481.2; Found 481.1.

Example 291.2-Methoxy-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinonitrile

This compound was prepared according to the procedures described inExample 1, using 4-chloro-2-methoxynicotinonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₁H₂₂F₃N₈O₃S (M+H)⁺: m/z=523.1; Found 523.1. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆, 1:1 rotamers) δ 8.69 (s, 0.5H), 8.63 (m, 1.5H), 8.55 (s, 0.5H),8.45 (s, 1H), 8.30 (s, 0.5H), 8.02 (m, 1H), 7.58 (d, J=5.5 Hz, 0.5H),7.52 (d, J=5.4 Hz, 0.5H), 4.10 (s, 3H), 4.01 (br, 1H), 3.56 (d, J=12.2Hz, 2H), 2.91 (m, 2H), 2.88 (s, 3H), 2.00 (m, 2H), 1.59 (m, 2H).

Example 292.3-Methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inExample 1, using 4-chloro-3-methylpicolinonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₁H₂₂F₃N₈O₂S (M+H)⁺: m/z=507.2; Found 507.2. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆, 1:1 rotamers) δ 8.79 (m, 1H), 8.68 (s, 0.5H), 8.62 (s, 0.5H),8.31 (s, 0.5H), 8.23 (s, 1H), 8.10 (s, 0.5H), 7.95 (m, 2H), 4.01 (br,1H), 3.55 (m, 2H), 2.89 (m, 5H), 2.47 (s, 3H), 1.97 (m, 2H), 1.60 (m,2H).

Example 293.2-Methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinonitrile

This compound was prepared according to the procedures described inExample 1, using 4-chloro-2-methylnicotinonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₁H₂₂F₃N₈O₂S (M+H)⁺: m/z=507.2; Found 507.2. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆, 1:1 rotamers) δ 8.90 (m, 1H), 8.67 (m, 1H), 8.53 (s, 0.5H),8.42 (s, 1H), 8.29 (s, 0.5H), 8.02 (m, 1H), 7.77 (m, 1H), 4.02 (br, 1H),3.56 (m, 2H), 2.88 (m, 5H), 2.80 (s, 3H), 2.02 (m, 2H), 1.60 (m, 2H).

TABLE 24 The compounds in Table 24 were prepared in accordance with thesynthetic protocols set forth in Example 1 using the appropriatestarting materials. Ex. Name Structure Analytical data 2943-Fluoro-2-(4-(2-((1- (methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol- 1-yl)benzonitrile

LCMS found 510.1 295 4-(1-(3-Chloro-2- methoxypyridin-4-yl)-1H-imidazol-4-yl)-N- (1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 532.1 296 4-(1-(3-Chloro-2- methylpyridin-4-yl)-1H-imidazol-4-yl)-N- (1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 516.0 297 4-(4-(2-(((3R,4S)-3- Fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol- 1-yl)-2- methoxynicotinonitrile

LCMS found 541.1 298 N-((3R,4S)-3-Fluoro-1- (methylsulfonyl)piperidin-4-yl)-4-(1-(3- fluoropyridin-4-yl)-2- methyl-1H-imidazol-4- yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 518.1 299 3-Fluoro-4-(4-(2- (((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H- imidazol-1- yl)benzonitrile

LCMS found 542.3 ¹H NMR (TFA salt, 600 MHz, DMSO-d₆, 1:1 rotamers) δ8.66 (s, 0.5H), 8.63 (s, 0.5H), 8.27 (m, 1H), 8.18 (s, 0.5H), 7.99 (m,3.5H), 4.99 (s, 0.5H), 4.90 (s, 0.5H), 4.21 (m, 1H), 3.83 (m, 1H), 3.65(m, 1H), 3.21 (m, 1H), 3.00 (m, 1H), 2.92 (m, 3H), 2.29 (m, 3H), 1.97(m, 1H), 1.80 (m, 1H)

Example 300.4-(1-(3-Chloro-2-methoxypyridin-4-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 1, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand 3,4-dichloro-2-methoxypyridine instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₀H₂₁ClF₄N₇O₃S (M+H)⁺: m/z=550.1; Found 550.1. H NMR (TFA salt, 500MHz, DMSO-d₆, 1:1 rotamers) δ 8.67 (d, J=16.3 Hz, 1H), 8.34 (m, 1.5H),8.24 (d, J=7.4 Hz, 1H), 8.18 (s, 0.5H), 8.62 (s, 0.5H), 8.07 (m, 1H),7.38 (m, 1H), 4.95 (m, 1H), 4.21 (m, 1H), 4.04 (s, 3H), 3.85 (m, 1H),3.67 (d, J=12.0 Hz, 1H), 3.22 (m, 1H), 3.01 (t, J=11.4 Hz, 1H), 2.92 (s,3H), 1.98 (m, 1H), 1.81 (m, 1H).

Example 301.4-(1-(3-Chloro-2-methylpyridin-4-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 1, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand 3,4-dichloro-2-methylpyridine instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₀H₂₁ClF₄N₇O₂S (M+H)⁺: m/z=534.1; Found 534.1. ¹H NMR (TFA salt, 500MHz, DMSO-d₆, 1:1 rotamers) δ 8.64 (m, 2H), 8.36 (s, 0.5H), 8.22 (t,J=6.9 Hz, 1H), 8.16 (s, 0.5H), 8.07 (m, 1H), 7.63 (m, 1H), 4.96 (m, 1H),4.23 (m, 1H), 3.84 (m, 1H), 3.66 (d, J=12.9 Hz, 1H), 3.22 (m, 1H), 3.01(t, J=11.5 Hz, 1H), 2.92 (s, 3H), 2.70 (s, 3H), 1.98 (m, 1H), 1.80 (m,1H).

Example 302.4-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-methylpicolinonitrile

This compound was prepared according to the procedures described inExample 1, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand 4-chloro-3-methylpicolinonitrile instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₁H₂₁F₄N₈O₂S (M+H)⁺: m/z=525.1; Found 525.2. ¹H NMR (TFA salt, 500 MHz,DMSO-d₆, 1:1 rotamers) δ 8.80 (m, 1H), 8.68 (m, 1H), 8.36 (s, 0.5H),8.23 (s, 1H), 8.12 (m, 1H), 8.03 (m, 0.5H), 7.93 (m, 1H), 4.99 (m, 1H),4.21 (m, 1H), 3.85 (m, 1H), 3.68 (m, 1H), 3.22 (m, 1H), 3.01 (m, 1H),2.93 (s, 3H), 2.50 (s, 3H), 1.98 (m, 1H), 1.81 (m, 1H).

Example 303.3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 1, using4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 38) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand 3,4-difluorobenzonitrile instead of 3-chloro-4-fluorobenzonitrile asstarting material. LCMS calculated for C₂₂H₂₂F₄N₇O₂S (M+H)⁺: m/z=524.1;Found 524.1. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1 rotamers) δ 8.66(s, 0.5H), 8.61 (s, 0.5H), 8.27 (m, 1H), 8.14 (s, 0.5H), 7.96 (m, 2.5H),4.02 (m, 1H), 3.55 (m, 2H), 2.88 (m, 5H), 2.31 (s, 3H), 1.97 (m, 2H),1.60 (m, 2H).

Example 304.2-Fluoro-3-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

Step 1:4-(1-(3-Bromo-2-fluoro-4-nitrophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures describe inExample 1, using4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 38) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand 2-bromo-3,4-difluoro-1-nitrobenzene instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₂₁H₂₁BrF₄N₇O₄S (M+H)⁺: m/z=622.0; Found 622.0.

Step 2:4-(1-(4-Amino-3-bromo-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of4-(1-(3-bromo-2-fluoro-4-nitrophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(130 mg, 0.21 mmol), iron powder (58.3 mg, 1.04 mmol), ammonium chloride(112 mg, 2.09 mmol) in tetrahydrofuran (4 mL), water (1 mL) and methanol(2 mL) was stirred at 55° C. for 3 hours. Upon cooling to roomtemperature, to the reaction was added dichloromethane (20 mL), then wasfiltered and washed with dichloromethane. The filtrate was concentratedand then purified by flash column chromatography(methanol/dichloromethane) to afford the desired product. LCMScalculated for C₂₁H₂₃BrF₄N₇O₂S (M+H)⁺: m/z=592.1; Found 592.1.

Step 3:4-(1-(3-Bromo-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A solution of4-(1-(4-amino-3-bromo-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(100 mg, 0.17 mmol) and tert-butyl nitrite (30.1 μL, 0.25 mmol) in THE(3 mL) was stirred at 65° C. for 4 hours. Upon cooling to roomtemperature, the reaction was concentrated and then purified by flashcolumn chromatography (methanol/dichloromethane) to afford the desiredproduct. LCMS calculated for C₂₁H₂₂BrF₄N₆O₂S (M+H)⁺: m/z=577.1; Found576.9.

Step 4:2-Fluoro-3-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

A mixture of4-(1-(3-bromo-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(163 mg, 0.282 mmol), Zn(CN)₂ (66.3 mg, 0.565 mmol) and tBuXPhos Pd G3(44.8 mg, 0.056 mmol) in DMF (4 mL) was stirred at 80° C. for 3 h. Aftercooling to r.t., the resultant mixture was diluted with acetonitrile andfiltered. The solution containing the desired product was then purifiedby prep-LCMS (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the product. LCMS calculated for C₂₂H₂₂F₄N₇O₂S (M+H)⁺: m/z=524.1;Found 524.1. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1 rotamers) δ 8.63(m, 1H), 8.12 (m, 2.5H), 7.94 (m, 1.5H), 7.63 (m, 1H), 4.02 (m, 1H),3.54 (m, 2H), 2.87 (m, 5H), 2.30 (s, 3H), 1.96 (m, 2H), 1.60 (m, 2H).

Example 305.2-Fluoro-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 304, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 39) instead of4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₂₂H₂₁F₅N₇O₂S (M+H)⁺:m/z=542.1; Found 542.1. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 4:6rotamers) δ 8.66 (m, 1H), 8.30-7.90 (m, 4H), 7.65 (m, 1H), 4.95 (d,J=48.8 Hz, 1H), 4.22 (m, 1H), 3.84 (m, 1H), 3.66 (d, J=12.5 Hz, 1H),3.21 (m, 1H), 3.01 (t, J=12.0 Hz, 1H), 2.92 (s, 3H), 2.30 (s, 3H), 1.96(m, 1H), 1.80 (m, 1H).

Example 306.3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)-2-methylbenzonitrile

This compound was prepared according to the procedures described inExample 42, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 39) instead ofN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₂₃H₂₄F₄N₇O₂S (M+H)⁺:m/z=538.2; Found 538.1. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1rotamers) δ 8.66 (m, 1H), 8.13 (s, 0.5H), 8.03 (m, 2H), 7.85 (m, 1.5H),7.64 (m, 1H), 4.95 (m, 1H), 4.22 (m, 1H), 3.82 (m, 1H), 3.65 (m, 1H),3.21 (m, 1H), 3.00 (m, 1H), 2.92 (d, J=6.9 Hz, 3H), 2.20 (m, 6H), 1.96(m, 1H), 1.80 (m, 1H).

Example 307.3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

Step 1:4-(1-(2,3-Dichloropyridin-4-yl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 1, using 2,3,4-trichloropyridine instead of3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated forC₁₉H₁₉Cl₂F₃N₇O₂S (M+H)⁺: m/z=536.1; Found 536.0.

Step 2:3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inExample 304, Step 4, using4-(1-(2,3-dichloropyridin-4-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineinstead of4-(1-(3-bromo-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₂₀H₁₉ClF₃N₈O₂S (M+H)⁺:m/z=527.1; Found 527.0. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1rotamers) δ 8.90 (m, 1H), 8.69 (s, 0.5H), 8.63 (s, 0.5H), 8.36 (s,0.5H), 8.28 (d, J=1.3 Hz, 1H), 8.18 (m, 1.5H), 8.13 (m, 1H), 8.00 (d,J=6.8 Hz, 1H), 4.01 (br, 1H), 3.56 (br, 2H), 2.89 (m, 5H), 1.98 (br,2H), 1.61 (br, 2H).

Example 308.3-Chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile

This compound was prepared according to the procedures described inExample 307, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 17) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₂₀H₁₈ClF₄N₈O₂S (M+H)⁺:m/z=545.1; Found 545.1. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1rotamers) δ 8.91 (m, 1H), 8.69 (m, 1H), 8.41 (s, 0.5H), 8.29 (s, 1H),8.24 (s, 0.5H), 8.16 (m, 2H), 8.08 (m, 1H), 4.98 (m, 1H), 4.21 (m, 1H),3.86 (m, 1H), 3.67 (m, 1H), 3.23 (m, 1H), 3.02 (m, 1H), 2.93 (s, 3H),1.98 (m, 1H), 1.81 (m, 1H).

TABLE 25 The compounds in Table 25 were prepared in accordance with thesynthetic protocols set forth in Example 307 using the appropriatestarting materials. Analytical Ex. Name Structure data 3093-Fluoro-4-(2-methyl- 4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)picolinonitrile

LCMS found 525.1 310 3-Fluoro-4-(4-(2- (((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H- imidazol-1- yl)picolinonitrile

LCMS found 543.0

Example 311.N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(3-fluoro-2-methoxypyridin-4-yl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 39, usingN-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 39) instead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand 2,3,4-trifluoropyridine instead of 6-chloro-3-fluoropicolinonitrileas starting material. LCMS calculated for C₂₁H₂₃F₅N₇O₃S (M+H)⁺:m/z=548.2; Found 548.1. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1rotamers) δ 8.66 (m, 1H), 8.18 (m, 2H), 8.06 (m, 1H), 7.98 (s, 1H), 7.37(m, 1H), 4.99 (s, 0.5H), 4.91 (s, 0.5H), 4.21 (m, 1H), 4.04 (s, 3H),3.83 (m, 1H), 3.66 (m, 1H), 3.21 (m, 1H), 3.01 (m, 1H), 2.92 (s, 3H),2.35 (s, 31), 1.97 (m, 1H), 1.80 (min, 1H).

TABLE 26 The compounds in Table 26 were prepared in accordance with thesynthetic protocols set forth in Example 42 using the appropriatestarting materials. Analytical Ex. Name Structure data 3124-(1-(2-Methoxy-3- methylpyridin-4-yl)- 1H-imidazol-4-yl)-N- (1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 512.0 313 N-((3R,4S)-3-Fluoro-1- (methylsulfonyl)piperidin-4-yl)-4-(1-(3-fluoro- 2-methylpyridin-4-yl)- 2-methyl-1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 532.1

TABLE 27 The compounds in Table 27 were prepared in accordance with thesynthetic protocols set forth in Example 39 using the appropriatestarting materials. Analytical Ex. Name Structure data 3144-(1-(3-Fluoro-2- methoxypyridin-4-yl)- 2-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 530.2 315 2-(4-Ethylpiperazin-1- yl)-4-(4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol- 1-yl)nicotinonitrile

LCMS found 605.3 316 2-(4-Methylpiperazin- 1-yl)-4-(4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol- 1-yl)nicotinonitrile

LCMS found 591.2 317 4-(4-(2-((1- (Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol- 1-yl)-2-morpholinonicotinonitrile

LCMS found 578.2 318 4-(1-(3-Chloro-2-(4- ethylpiperazin-1-yl)pyridin-4-yl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 614.1 319 4-(1-(3-Chloro-2-(4- methylpiperazin-1-yl)pyridin-4-yl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 600.2 320 4-(1-(3-Chloro-2- morpholinopyridin-4-yl)-1H-imidazol-4-yl)- N-(1- (methylsulfonyl)piperidin- 4-yl)-5-trifluoromethyl)pyrimidin- 2-amine

LCMS found 587.2 321 4-(1-(3-Chloro-2- (dimethylamino)pyridin-4-yl)-1H-imidazol-4- yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 545.1 322 4-(1-(3-Chloro-2- (methylamino)pyridin-4-yl)-1H-imidazol-4- yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 531.1

Example 323.1-(4-(2-(((3R,4S)-1-(Cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol

Step 1:N-((3R,4S)-1-(Cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)-4-(H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 17, using cyclopropanesulfonyl chloride instead ofmethanesulfonyl chloride as starting material. LCMS calculated forC₁₆H₁₉F₄N₆O₂S (M+H)⁺: m/z=435.1; Found 435.1.

Step 2:1-(4-(2-(((3R,4S)-1-(Cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol

This compound was prepared according to the procedures described inExample 21, usingN-((3R,4S)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineinstead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand 2,2-dimethyloxirane instead of 1,1-difluoro-2-iodoethane as startingmaterial. LCMS calculated for C₂₀H₂₇F₄N₆O₃S (M+H)⁺: m/z=507.2; Found507.2. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1 rotamers) δ 8.69 (m, 1H),8.34 (br, 0.5H), 8.19 (br, 0.5H), 8.04 (m, 1.5H), 7.92 (s, 0.5H), 4.97(m, 1H), 4.30 (m, 1H), 4.15 (s, 1H), 4.05 (s, 1H), 3.91 (br, 1H), 3.71(m, 1H), 3.26 (m, 1H), 3.07 (m, 1H), 2.62 (m, 1H), 2.00 (m, 1H), 1.81(br, 1H), 1.12 (s, 3H), 1.09 (s, 3H), 1.00 (m, 4H).

Example 324.1-(4-(2-((1-(Ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol

Step 1:N-(1-(Ethylsulfonyl)piperidin-4-yl)-4-(H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 2, using ethanesulfonyl chloride instead of methanesulfonylchloride as starting material. LCMS calculated for C₁₅H₂₀F₃N₆O₂S (M+H)⁺:m/z=405.1; Found 405.1.

Step 2:1-(4-(2-((1-(Ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol

This compound was prepared according to the procedures described inExample 21, usingN-(1-(ethylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineinstead of4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand 2,2-dimethyloxirane instead of 1,1-difluoro-2-iodoethane as startingmaterial. LCMS calculated for C₁₉H₂₈F₃N₆O₃S (M+H)⁺: m/z=477.2; Found477.3. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆, 1:1 rotamers) δ 8.65 (br,2H), 8.18 (br, 0.5H), 8.01 (m, 1H), 7.88 (s, 0.5H), 4.11 (m, 3H), 3.62(d, J=12.2 Hz, 2H), 3.07 (m 2H), 2.98 (d, J=6.7 Hz, 2H), 1.94 (m, 2H),1.58 (m, 2H), 1.23 (t, J=7.3 Hz, 3H), 1.12 (s, 3H), 1.09 (s, 3H).

TABLE 28 The compounds in Table 28 were prepared in accordance with thesynthetic protocols set forth in Example 21 using the appropriatestarting materials. Analytical Ex. Name Structure data 3251-(4-(2-(((3R,4S)-3- Fluoro-1- (methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol- 1-yl)-2-methylpropan-2-ol

LCMS found 481.2 326 1-(4-(2-(((3R,4R)-3- Fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol- 1-yl)-2-methylpropan- 2-ol

LCMS found 481.2 327 2-Methyl-1-(4-(2- (((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol- 1-yl)propan-2-ol

LCMS found 477.2 328 4-(1-(2,2- Difluoroethyl)-1H- imidazol-4-yl)-N-(1-(ethylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 469.0 329 N-((3R,4S)-1- (Cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)- 4-(1-(2,2- difluoroethyl)-1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 499.0 330 4-(1-(2,2- Difluoroethyl)-1H- imidazol-4-yl)-N-((3R,4S)-3-fluoro-1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 473.0 331 4-(1-(2,2- Difluoroethyl)-1H- imidazol-4-yl)-N-((3R,4R)-3-fluoro-1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 473.0 332 1-(4-(2-(((3R,4S)-1- (Cyclopropylsulfonyl)-3-methylpiperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol- 1-yl)-2-methylpropan- 2-ol

LCMS found 503.1

TABLE 29 The compounds in Table 29 were prepared in accordance with thesynthetic protocols set forth in Example 87 using the appropriatestarting materials. Analytical Ex. Name Structure data 3331-(4-(2-(((3R,4R)-1- (Cyclopropylsulfonyl)- 3-fluoropiperidin-4-yl)amino)-5- 4-yl)-1H-imidazol- 1-yl)-2-methylpropan- 2-ol

LCMS found 507.2 334 4-(1-(2,2- Difluoroethyl)-1H- imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol- 4-yl)sulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 521.1 335 1-(4-(2-(((3R,4R)-3- Fluoro-1-((1-methyl-1H-pyrazol-3- yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol- 1-yl)-2-methylpropan-2-ol

LCMS found 547.2 336 1-(4-(2-(((3R,4R)-3- Fluoro-1-((1-methyl-1H-pyrazol-4- yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol- 1-yl)-2-methylpropan-2-ol

LCMS found 547.1 337 4-(1-(2,2- Difluoroethyl)-1H- imidazol-4-yl)-N-((3R,4S)-3-methyl-1- ((1-methyl-1H- imidazol-4- yl)sulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 535.1 338 2-Methyl-1-(4-(2-((1- (pyridin-2-ylsulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol- 1-yl)propan-2-ol

LCMS found 526.1

Example 339.5-((4-Ethylpiperazin-1-yl)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

Step 1:5-Formyl-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 250, Step 1, using 2-fluoro-5-formylbenzonitrile instead of4-fluoro-3-(trifluoromethyl)benzaldehyde as starting material. LCMScalculated for C₂₂H₂₁F₃N₇O₃S (M+H)⁺: m/z=520.1; Found 520.1.

Step 2:5-((4-Ethylpiperazin-1-yl)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 175, using5-formyl-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrileinstead of3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehydeand 1-ethylpiperazine instead of dimethylamine as starting material.LCMS calculated for C₂₈H₃₅F₃N₉O₂S (M+H)⁺: m/z=618.3; Found 618.3. ¹H NMR(TFA salt, 500 MHz, DMSO-d₆, 1:1 rotamers) δ 8.69 (s, 0.5H), 8.63 (s,0.5H), 8.41 (s, 0.5H), 8.28 (s, 1H), 8.16 (s, 0.5H), 8.06 (s, 1H), 7.98(m, 1H), 7.86 (br, 1.5H), 7.81 (m, 0.5H), 4.02 (br, 1H), 3.74 (s, 2H),3.56 (br, 2H), 3.48 (d, J=11.7 Hz, 2H), 3.15 (d, J=7.1 Hz, 2H), 2.96 (m,6H), 2.87 (s, 3H), 2.43 (m, 2H), 2.01 (m, 2H), 1.60 (m, 2H), 1.22 (t,J=7.2 Hz, 3H).

Example 340.5-((Isopropylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 339, using propan-2-amine instead of 1-ethylpiperazine asstarting material. LCMS calculated for C₂₅H₃₀F₃N₈O₂S (M+H)⁺: m/z=563.2;Found 563.1. ¹H NMR (TFA salt, 600 MHz, DMSO-d₆, 1:1 rotamers) δ 8.83(s, 1H), 8.69 (s, 0.5H), 8.64 (s, 0.5H), 8.45 (s, 0.5H), 8.34 (s, 1H),8.25 (s, 1H), 8.21 (s, 0.5H), 7.98 (m, 3H), 4.33 (s, 2H), 4.02 (br, 1H),3.56 (br, 2H), 3.37 (m, 1H), 2.90 (m, 2H), 2.87 (s, 3H), 1.99 (m, 2H),1.61 (m, 2H), 1.31 (d, J=6.5 Hz, 6H).

TABLE 30 The compounds in Table 30 were prepared in accordance with thesynthetic protocols set forth in Example 175 using the appropriatestarting materials. Ex. Name Structure Analytical data 341 5-((Ethylamino)methyl)- 2-(4-(2-((1- (methylsulfonyl)piperidin-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H- imidazol-1-yl)benzonitrile

LCMS found 549.0 ¹H NMR (TFA salt, 600 MHz, DMSO-d₆, 1:1 rotamers) δ8.90 (br, 1H), 8.69 (s, 0.5H), 8.63 (s, 0.5H), 8.45 (s, 0.5H), 8.33 (s,1H), 8.22 (br, 1.5H), 7.96 (m, 3H), 4.31 (m, 2H), 4.02 (m, 1H), 3.56 (m,2H), 3.02 (m, 2H), 2.90 (m, 5H), 2.00 (m, 2H), 1.61 (m, 2H), 1.24 (t, J= 7.2 Hz, 3H) 342 (R)-5-((3- Hydroxypyrrolidin-1-yl)methyl)-2-(4-(2-((1- (methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H- imidazol-1- yl)benzonitrile

LCMS found 591.1 343 5- ((Cyclopropylamino) methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H- imidazol-1- yl)benzonitrile

LCMS found 561.1 344 5-((4- Methylpiperazin-1- yl)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H- imidazol-1- yl)benzonitrile

LCMS found 604.1 345 2-(4-(2-((1- (Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H- imidazol-1-yl)-5-(piperidin-1- ylmethyl)benzonitrile

LCMS found 589.1 346 2-(4-(2-((1- (Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H- imidazol-1-yl)-5-(pyrrolidin-1- ylmethyl)benzonitrile

LCMS found 575.0 347 4-(1-(4- ((Cyclopropylamino) methyl)-2,6-difluorophenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 572.0 348 4-(1-(2,6-Difluoro-4- ((isopropylamino)methylphenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 574.0 349 4-(1-(4- ((Ethylamino)methyl)- 2,6-difluorophenyl)-1H-imidazol-4-yl)-N- (1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 560.0 ¹H NMR (TFA salt, 600 MHz, DMSO-d₆, 1:1 rotamers) δ8.98 (br, 1H), 8.68 (s, 0.5H), 8.62 (s, 0.5H), 8.22 (s 0.5H) 8.18 (s,1H), 8.05 (s, 0.5H), 7.98 (m, 1H), 7.59 (m, 2H), 4.29 (s, 2H), 4.02 (m,1H), 3.54 (m, 2H), 3.01 (m, 2H), 2.90 (m, 5H), 1.98 (m, 2H), 1.60 (m,2H), 1.24 (t, J = 7.2 Hz, 3H) 350 4-(1-(2,6-Difluoro-4-((methylamino)methyl) phenyl)-1H-imidazol- 4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 546.0 351 4-(1-(4-((4- Ethylpiperazin-1- yl)methyl)-2,6-difluorophenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 629.1 ¹H NMR (TFA salt, 600 MHz, DMSO-d₆, 1:1 rotamers) δ9.29 (br, 1H), 8.68 (s, 0.5H), 8.62 (s, 0.5H), 8.21 (s, 0.5H), 8.13 (s,1H), 8.00 (s, 0.5H), 7.96 (m, 1H), 7.42 (m, 2H), 4.03 (m, 1H), 3.70 (s,2H), 3.54 (m, 2H), 3.48 (m, 2H), 3.15 (m, 2H), 3.04 (m, 2H), 2.98 (m,2H), 2.90 (m, 5H), 2.42 (t, J = 12.1 Hz, 2H), 1.98 (m, 2H), 1.59 (m,2H), 1.23 (t, J = 7.3 Hz, 3H) 352 4-(1-(2,6-Difluoro-4-((4-methylpiperazin-1- yl)methyl)phenyl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 615.0 353 4-(1-(2-Fluoro-4-((3- methoxyazetidin-1-yl)methyl)phenyl)-2- methyl-1H-imidazol- 4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 598.0 354 1-(3-Fluoro-4-(2- methyl-4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H- imidazol-1-yl)benzyl)- 3-methylazetidin-3-ol

LCMS found 598.0 355 1-(3-Fluoro-4-(2- methyl-4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H- imidazol-1- yl)benzyl)azetidin-3-ol

LCMS found 584.0 356 4-(1-(4- ((Cyclopropylamino) methyl)-2-fluorophenyl)-2- methyl-1H-imidazol- 4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 568.0 357 4-(1-(4- ((Diethylamino)methyl)- 2-fluorophenyl)-2-methyl-1H-imidazol- 4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 584.1 358 4-(1-(4- ((Ethyl(methyl)amino) methyl)-2-fluorophenyl)-2- methyl-1H-imidazol- 4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 570.0 359 4-(1-(4- ((Ethylamino)methyl)- 2-fluorophenyl)-2-methyl-1H-imidazol- 4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 556.0 ¹H NMR (TFA salt, 600 MHz, DMSO-d₆, 1:1 rotamers) δ8.90 (br, 1H), 8.65 (s, 0.5H), 8.59 (s, 0.5H), 8.02 (s, 0.5H), 7.91 (d,J = 7.9 Hz, 1H), 7.80 (m, 1.5H), 7.70 (d, J = 10.7 Hz, 1H), 7.54 (br,1H), 4.28 (s, 2H), 4.01 (m, 1H), 3.54 (m, 2H), 3.04 (m, 2H), 2.88 (m,5H), 2.26 (s, 3H), 1.96 (m, 2H), 1.59 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H)

TABLE 31 The compounds in Table 31 were prepared in accordance with thesynthetic protocols set forth in Example 77 using the appropriate aminestarting material. Ex. Name Structure Analytical data 3604-(1-(2-Chloro-3- ((isopropylamino)meth- yl)phenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimi- din-2-amine

LCMS found 572.3 361 4-(1-(2-Chloro-3- ((ethylamino)methyl)phe-nyl)-1H-imidazol-4- yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimi- din-2-amine

LCMS found 558.3 362 1-(2-Chloro-3-(4-(2- ((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimi-din-4-yl)-1H-imidazol- yl)benzyl)-3- methylazetidin-3-ol

LCMS found 600.3 363 (R)-1-(2-Chloro-3-(4- (2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimi-din-4-yl)-1H-imidazol- 1-yl)benzyl)-3- methylpyrrolidin-3-ol

LCMS found 614.2 364 (R)-1-(2-Chloro-3-(4- (2-((1-(methyslulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimi-din-4-yl)-1H-imidazol- 1-yl)benzyl)pyrrolidin- 3-ol

LCMS found 600.2 365 (S)-1-(2-Chloro-3-(4- (2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimi-din-4-yl)-1H-imidazol- 1-yl)benzyl)pyrrolidin- 3-ol

LCMS found 600.2 366 4-(1-(3-(Azetidin-1- ylmethyl)-2- chlorophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimi- din-2-amine

LCMS found 570.3 367 4-(1-(2-Chloro-3- (((tetrahydrofuran-3-yl)amino)methyl)phenyl)- 1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimi- din-2-amine

LCMS found 600.3 368 4-(1-(2-Chloro-3- (((tetrahydro-2H- pyran-4-yl)amino)methyl)phenyl)- 1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimi- din-2-amine

LCMS found 614.4

Example 369.4-(1-(2-Chloro-3-(2-morpholinoethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:2-(2-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)acetaldehyde

This compound was prepared according to the procedures described inIntermediate 35, using 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane as startingmaterial for Step 1. LCMS calculated for C₂₂H₂₃ClF₃N₆O₃S (M+H)⁺:m/z=543.1; Found 543.1.

Step 2: 4-(1-(2-Chloro-3-(2-morpholinoethyl)phenyl)-NH-imidazol-4yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 77, using2-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)acetaldehydeand morpholine instead of2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehydeand dimethylamine as starting materials. LCMS calculated forC₂₆H₃₂ClF₃N₇O₃S (M+H)⁺: m/z=614.2; Found 614.2.

TABLE 32 The compounds in Table 32 were prepared in accordance with thesynthetic protocols set forth in Example 369 using the appropriate aminestarting material. Analytical Ex. Name Structure data 3704-(1-(2-Chloro-3-(2- (dimethylamino)ethyl)phe- nyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimi-din-2-amine

LCMS found 572.2 371 4-(1-(2-Chloro-3-(2- (cyclopropylamino)eth-yl)phenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimi- din-2-amine

LCMS found 584.2 372 1-(2-Chloro-3-(4-(2- ((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimi-din-4-yl)-1H-imidazol- 1-yl)phenethyl)-3- methylazetidin-3-ol

LCMS found 614.3 373 4-(1-(3-(2-(Azetidin-1- yl)ethyl)-2-chlorophenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimi- din-2-amine

LCMS found 584.3 374 (R)-1-(2-Chloro-3-(4- (2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimi-din-4-yl)-1H-imidazol- 1-yl)phenethyl)-3- methylpyrrolidin-3-ol

LCMS found 628.3

Example 375.4-(1-(2-Chloro-3-(1-(ethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:1-(2-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethan-1-one

This compound was prepared according to the procedures described inIntermediate 35, using4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane instead of4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane as starting material forStep 1. LCMS calculated for C₂₂H₂₃ClF₃N₆O₃S (M+H)⁺: m/z=543.1; Found543.0.

Step 2:4-(1-(2-Chloro-3-(1-(ethylamino)ethyl)phenyl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 175, using1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethan-1-oneand ethanamine instead of3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehydeand dimethylamine as starting materials. LCMS calculated forC₂₄H₃₀ClF₃N₇O₂S (M+H)⁺: m/z=572.2; Found 572.3.

TABLE 33 The compounds in Table 33 were prepared in accordance with thesynthetic protocols set forth in Example 375 using the appropriate aminestarting material. Analytical Ex. Name Structure data 3764-(1-(2-Chloro-3-(1- (dimethylamino)ethyl)phe- nyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimi-din-2-amine

LCMS found 572.3 377 4-(1-(2-Chloro-3-(1- (methylamino)ethyl)phe-nyl)-1H-imidazol-4- yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimi- din-2-amine

LCMS found 558.2

Example 378.4-(1-(3-((Methylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 3, using 3-fluoro-2-(trifluoromethyl)benzaldehyde instead of3-chloro-4-fluorobenzaldehyde as the starting material for Step 1. LCMScalculated for C₂₃H₂₆F₆N₇O₂S (M+H)⁺: m/z=578.2; Found 578.4.

TABLE 34 The compounds in Table 34 were prepared in accordance with thesynthetic protocols set forth in Example 378 using the appropriate aminestarting material. Analytical Ex. Name Structure data 3793-Methyl-1-(3-(4-(2- ((1- (methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimi- din-4-yl)-1H-imidazol- 1-yl)-2-(trifluoromethyl)benzyl) azetidin-3-ol

LCMS found 634.4 380 4-(1-(3-(Azetidin-1- ylmethyl)-2-(trifluoromethyl)phenyl)- 1H-imidazol-4-yl)-N- (1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimi- din-2-amine

LCMS found 604.4 381 (R)-3-Methyl-1-(3-(4- (2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimi-din-4-yl)-1H-imidazol- 1-yl)-2- (trifluoromethyl)benzyl) pyrrolidin-3-ol

LCMS found 648.4

Example 382.4-(1-(2-Methyl-6-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 250, using 5-fluoro-6-methylpicolinaldehyde instead of4-fluoro-3-(trifluoromethyl)benzaldehyde for Step 1 and piperidineinstead of dimethylamine as the starting material for Step 2. LCMScalculated for C₂₆H₃₄F₃N₈O₂S (M+H)⁺: m/z=579.3; Found 579.4.

Example 383.4-(5-Bromo-1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:4-Chloro-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 4, using 1-methyl-1H-pyrazole-4-sulfonyl chloride insteadof 1-methyl-1H-imidazole-4-sulfonyl chloride as starting material. LCMScalculated for C₁₄H₁₇ClF₃N₆O₂S (M+H)⁺: m/z=425.1; Found 425.2.

Step 2:4-(1-Methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 10, using4-chloro-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineinstead of4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₈H₂₂F₃N₈O₂S (M+H)⁺:m/z=471.2; Found 471.2.

Step 3:4-(5-Bromo-1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 13, using4-(1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineinstead of4-(1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₁₈H₂₁BrF₃N₈O₂S (M+H)⁺:m/z=549.1; Found 549.1.

TABLE 35 The compounds in Table 35 were prepared in accordance with thesynthetic protocols set forth in Example 1 using the appropriatestarting materials. Analytical Ex. Name Structure data 3842-Chloro-3-(4-(2- (((3R,4S)-3-fluoro-1- (methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimi- din-4-yl)-2-methyl-1H-imidazol-1- yl)benzonitrile

LCMS found 558.1

TABLE 36 The compounds in Table 36 were prepared in accordance with thesynthetic protocols set forth in Example 175 using the appropriatestarting materials. Analytical Ex. Name Structure data 3854-(1-(2-Fluoro-4- ((isopropylamino)methyl)- 6-methylphenyl)-1H-imidazol-4-yl)-N-(1- (methyslulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 570.2 386 4-(1-(2,6-Difluoro-4- ((isopropylamino)methyl)phenyl)-1H-imidazol-4- yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 592.1 387 N-((3R,4S)-3-Fluoro-1- (methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4-((4- methylpiperazin-1- yl)methyl)phenyl)-2-methyl-1H-imidazol-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 629.2 388 N-((3R,4S)-3-Fluoro-1- (methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4- ((isoporopylamino)methyl) phenyl)-2-methyl-1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 588.1 389 4-(1-(4- ((Ethylamino)methyl)-2-fluorophenyl)-2-methyl- 1H-imidazol-4-yl)-N- ((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 574.2 390 4-(1-(4- ((Ethylamino)methyl)-2,6-difluorophenyl)-1H- imidazol-4-yl)-N- ((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 578.2 391 4-(1-(2,6-Difluoro-4- ((isopropylamino)methyl)phenyl)-1H-imidazol-4- yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 592.2 392 4-(1-(4-((4- Ethylpiperazin-1- yl)methyl)-2,6-difluorophenyl)-1H- imidazol-4-yl)-N- ((3R,4R)-3-fluoro-1-(methyslulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 647.3 393 4-(1-(2-Chloro-4- ((ethylamino)methyl)-6-fluorophenyl)-1H- imdazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 576.2 394 4-(1-(2-Chloro-6-fluoro-4- ((isopropylamino)methyl)phenyl)-1H-imidazol-4- yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS found 590.2 395 4-(1-(4-(Azetidin-1- ylmethyl)-2-chloro-6-fluorophenyl)-1H- imidazol-4-yl)-N-(1- (methyslulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 588.1 396 4-(1-(2-Chloro-4-((4- ethylpiperazin-1-yl)methyll)-6- fluorophenyl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 645.2 397 (R)-1-(3-Chloro-4-(4-(2- (((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)benzyl)-3- methylpyrrolidin-3-ol

LCMS found 632.2 398 4-(1-(2-Chloro-4-((4- ethylpiperazin-1-yl)methyl)phenyl)-1H- imidazol-4-yl)-N- ((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 645.3 399 4-(1-(4-(Azetidin-1- ylmethyl)-2- chlorophenyl)-1H-imidazol-4-yl)-N- ((3R,4R)-3-fluoro-1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 588.1 400 4-(1-(2-Chloro-4- ((isopropylamino)methyl)phenyl)-1H-imidazol-4- yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 590.2 401 4-(1-(2-Chloro-4- ((ethylamino)methyl)phenyl-1H-imidazol-4-yl)-N- ((3R,4R)-3-fluoro-1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 576.1 402 (R)-1-(3-Chloro-5-fluoro- 4-(4-(2-(((3R,4R)-3-fluoro-1- (methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1- yl)benzyl)-3-methylpyrrolidin-3-ol

LCMS found 650.1 403 4-(1-(2-Chloro-4-((4- ethylpiperazin-1-yl)methyl)-6- fluorophenyl)-1H- imidazol-4-yl)-N- ((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 663.3 404 4-(1-(4-(Azetidin-1- ylmethyl)-2-chloro-6-fluorophenyl)-1H- imidazol-4-yl)-N- ((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 606.2 405 4-(1-(2-Chloro-6-fluoro-4- ((isopropylamino)methyl)phenyl)-1H-imidazol-4- yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 608.2 406 4-(1-(2-Chloro-4- ((ethylamino)methyl)-6-fluorophenyl)-1H- imidazol-4-yl)-N- ((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 594.1 407 N-((3R,4S)-3-Fluoro-1- (methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4- (pyrrolidin-1- ylmethyl)phenyl)-2-methyl-1H-imidazol-4- yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 600.2 408 4-(1-(4- ((Cyclopropylamino)meth-yl-2-fluorophenyl)-2- methyl-1H-imidazol-4- yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS found 586.1 409 4-(3,5-Difluoro-4-(4-(2- ((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)benzyl)-1- methylpiperazin-2-one

LCMS found 629.3 410 (S)-1-(3-Chloro-4-(4-(2- (((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)benzyl)-3- methylpyrrolidin-3-ol

LCMS found 632.4 411 (R)-1-(3-Chloro-4-(4-(2- (((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)benzyl)-3- methylpyrrolidin-3-ol

LCMS found 632.4 412 (S)-1-(3-Chloro-4-(4-(2- (((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)benzyl)-3- methylpyrrolidin-3-ol

LCMS found 632.4

TABLE 37 The compounds in Table 37 were prepared in accordance with thesynthetic protocols set forth in Example 101 using the appropriatestarting materials. Analytical Ex. Name Structure data 413 4-(1-(4-(4-(Diethylamino)piperidin- 1-yl)-2-fluorophenyl)- 2-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS [M + H]: found 653.3 414 4-(1-(2-Fluoro-4-(4-methyl-4-(pyrrolidin-1- yl)piperidin-1- yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS [M + H]: found 665.3 415 4-(1-(2-Fluoro-4-(4-(4- methylpiperazin-1-yl)piperidin-1- yl)phenyl)-2-methyl- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin- 2-amine

LCMS [M + H]: found 680.3

Example 416.4-(1-(4-(2-(Azetidin-1-yl)ethyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 157, using4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 41) and azetidine instead of4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineand dimethylamine as starting material. LCMS calculated forC₂₆H₃₂F₄N₇O₂S (M+H)⁺: m/z=582.2; Found 582.2.

Example 417.4-(1-(2-Fluoro-4-(1-methylazetidin-3-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of4-(1-(4-(azetidin-3-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Example 160, 19.2 mg, 0.035 mmol), formaldehyde (5.2 mg, 0.17 mmol) andacetic acid (2.0 μL, 0.035 mmol) in DCM (0.2 mL) was stirred at roomtemperature for 30 min. Then sodium triacetoxyborohydride (11 mg, 0.052mmol) was added. The mixture was further stirred at room temperature for1 h. The reaction was concentrated. The residue was then diluted withMeOH and filtered and the filtrate was purified by prep HPLC (SunfireC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min). ¹H NMR (600 MHz, DMSO-d₆, 1:1rotamers) δ 10.28-9.72 (m, 1H), 8.62 (m, 1H), 8.01-7.81 (m, 1H), 7.93(d, J=7.5 Hz, 1H), 7.79-7.64 (m, 2H), 7.48 (d, J=7.5 Hz, 1H), 4.56-4.39(m, 2H), 4.36-4.26 (m, 1H), 4.24-4.15 (m, 2H), 4.02 (m, 1H), 3.62-3.47(m, 2H), 3.02-2.87 (m, 5H), 2.86 (s, 3H), 2.27 (d, J=3.6 Hz, 3H),2.01-1.92 (m, 2H), 1.59 (s, 2H). LCMS calculated for C₂₅H₃F₄N₇O₂S(M+H)⁺: m/z=568.2; Found 568.2.

Example 418.4-(1-(4-(1-Ethylazetidin-3-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 157, using acetaldehyde instead of formaldehyde as startingmaterial. LCMS calculated for C₂₆H₃₂F₄N₇O₂S (M+H)⁺: m/z=582.2; Found582.2.

Example 419.(S)-1-(3-(3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)azetidin-1-yl)propan-2-ol

Step 1:(S)-4-(1-(4-(1-(2-((tert-Butyldimethylsilyl)oxy)propyl)azetidin-3-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 417, using (S)-2-((tert-butyldimethylsilyl)oxy)propanal insteadof formaldehyde as starting material. After completion, the reaction wasconcentration and purified by column chromatography (DCM/MeOH 0-10%gradient). LCMS calculated for C₃₃H₄₈F₄N₇O₃SSi (M+H)⁺: m/z=726.3; Found726.3.

Step 2:(S)-1-(3-(3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)azetidin-1-yl)propan-2-ol

(S)-4-(1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)propyl)azetidin-3-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(20 mg, 0.027 mmol) in THF (0.14 mL) was treated with TBAF (0.05 mL, 1.0M in THF). The mixture was further stirred at room temperature for 1 h.The reaction was concentrated. The residue was then diluted with MeOHand was purified by prep HPLC (Sunfire C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₇H₃₄F₄N₇O₃S (M+H)⁺: m/z=612.2; Found612.2.

TABLE 38 The compounds in Table 38 were prepared in accordance with thesynthetic protocols set forth in Example 419 using the appropriatestarting materials. Analytical Ex. Name Structure data 4202-(3-(3-Fluoro-4-(2- methyl-4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)phenyl)azetidin-1- yl)ethan-1-ol

LCMS [M + H]: found 598.2 421 (R)-1-(3-(3-Fluoro-4-(2- methyl-4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)phenyl)azetidin-1- yl)propan-2-ol

LCMS [M + H]: found 612.2 422 1-((3-(3-Fluoro-4-(2- methyl-4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)phenyl)azetidin-1- yl)methyl)cyclopropan-1- ol

LCMS [M + H]: found 624.2

Example 423.4-(1-(4-(2-(Dimethylamino)ethoxy)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a mixture of4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 41, 20 mg, 0.032 mmol) and 2-(dimethylamino)ethan-1-ol(5.7 mg, 0.064 mmol) in 1,4-dioxane (0.12 mL) was added[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (1.4 mg, 1.6 μmol) and sodium tert-butoxide (7.7 mg,0.080 mmol). The mixture was degassed with N₂ and then stirred in asealed vial at 70° C. for 6 h. After cooling to room temperature, thereaction mixture was concentrated. The residue was then diluted withMeOH, filtered to remove Pd residues and the filtrate was purified byprep HPLC (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₅H₃₂F₄N₇O₃S (M+H)⁺: m/z=586.2; Found 586.2.

TABLE 39 The compounds in Table 39 were prepared in accordance with thesynthetic protocols set forth in Example 423 using the appropriatestarting materials. Analytical Ex. Name Structure data 4244-(1-(2-Fluoro-4-(2- (pyrrolidin-1- yl)ethoxy)phenyl)-2-methyl-1H-imidazol-4- yl)-N-(1- (mehtylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS [M + H]: found 612.2 425 (S)-4-(1-(2-Fluoro-4-((1-methylpyrrolidin-2- yl)methoxy)phenyl)-2- methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS [M + H]: found 612.2 426 (R)-4-(1-(2-Fluoro-4-((1-methylpyrrolidin-2- yl)methoxy)phenyl)-2- methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS [M + H]: found 612.2

Example 427.5-(1-Isopropylazetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

Step 1:5-(Azetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

To a mixture of zinc dust (17.20 mg, 0.263 mmol) in THF (1 mL) was added1,2-dibromoethane (1.511 μL, 0.018 mmol) and TMSCl (2.225 μL, 0.018mmol). The mixture was sparged with N₂ and then stirred at 60° C. in asealed vial. After 15 minutes, to the mixture was added tert-butyl3-iodoazetidine-1-carboxylate (49.6 mg, 0.175 mmol) inN,N-dimethylacetamide (1 mL). The mixture continued to stir at 60° C.for an additional 15 minutes. After the reaction was cooled to roomtemperature, to the mixture was added5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile(Example 125, step 1, 100 mg, 0.175 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (7.2 mg, 8.8 μmol) and CuI (1.7mg, 8.8 μmol). The mixture was purged with N₂ and stirred at 80° C.overnight. After cooling to room temperature, the mixture was filteredthrough a short pad of celite and the filtrate was concentrated. Theresidue was then dissolved in DCM (0.20 mL) and treated withtrifluoroacetic acid (0.40 mL). The mixture was stirred at roomtemperature for 30 min. The reaction was concentrated and diluted withMeOH, then was purified by prep HPLC. LCMS calculated for C₂₄H₂₆F₃N₈O₂S(M+H)⁺: m/z=547.2; Found 547.2.

Step 2:5-(1-isopropylazetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

A mixture of5-(azetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile(10 mg, 0.018 mmol), propan-2-one (10.18 mg, 0.175 mmol) and acetic acid(2.74 μL, 0.048 mmol) in DCM (0.180 mL) was stirred at room temperaturefor 30 min. Then sodium triacetoxyborohydride (10.2 mg, 0.048 mmol) wasadded. The mixture was further stirred at room temperature for 1 h. Thereaction was concentrated. The residue was then diluted with MeOH,filtered and the filtrate was purified by prep HPLC (Sunfire C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₇H₃₂F₃N₈O₂S (M+H)⁺:m/z=589.2; Found 589.2.

TABLE 40 The compounds in Table 40 were prepared in accordance with thesynthetic protocols set forth in Example 427 using the appropriatestarting materials. Analytical Ex. Name Structure data 4285-(1-Methylazetidin-3- yl)-2-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-imidazol-1-yl) benzonitrile

LCMS [M + H]: found 561.2 429 5-(1-Ethylazetidin-3-yl)- 2-(4-(2-((1-(methylsulfonyl) piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol- 1-yl)benzonitrile

LCMS [M + H]: found 575.2

Example 430.5-(4-Methylpiperazin-1-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

To a mixture of5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile(Example 125, Step 1, 15 mg, 0.026 mmol) and 1-methylpiperazine (7.90mg, 0.079 mmol) in 1,4-dioxane (0.1 mL) was addedtris(dibenzylideneacetone)dipalladium(0):BINAP:sodium tert-butoxide(0.05:0.15:2 molar ratio) (13 mg). The mixture was degassed with N₂ andthen stirred in a sealed vial at 100° C. for 1 h. After cooling to roomtemperature, the reaction mixture was concentrated. The residue was thendiluted with MeOH, filtered to remove Pd residue and the filtrate waspurified by prep HPLC (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₆H₃₁F₃N₉O₂S (M+H)⁺: m/z=590.2; Found 590.2.

TABLE 41 The compounds in Table 41 were prepared in accordance with thesynthetic protocols set forth in Example 430 using the appropriatestarting materials. Analytical Ex. Name Structure data 4315-(Methyl(2-(methylamino) ethyl)amino)-2-(4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H- imidazol-1-yl)benzonitrile

LCMS [M + H]: found 578.2 432 5-((2-(Dimethylamino)ethyl)amino)-2-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl) pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

LCMS [M + H]: found 578.2

Example 433.5-(2-(Dimethylamino)ethyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 157, using5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile(Example 125, step 1) instead of4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₂₅H₃₀F₃N₈O₂S (M+H)⁺:m/z=563.2; Found 563.2.

TABLE 42 The compounds in Table 42 were prepared in accordance with thesynthetic protocols set forth in Example 433 using the appropriatestarting materials. Analytical Ex. Name Structure data 434 2-(4-(2-((1-(Methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5- (2-(pyrrolidin-1-yl)ethyl) benzonitrile

LCMS [M + H]: found 589.2

Example 435.5-(2-(Dimethylamino)ethoxy)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 423, using5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile(Example 125, step 1) instead of4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amineas starting material. LCMS calculated for C₂₅H₃₀F₃N₈O₃S (M+H)⁺:m/z=579.2; Found 579.2.

TABLE 43 The compounds in Table 43 were prepared in accordance with thesynthetic protocols set forth in Example 435 using the appropriatestarting materials. Analytical Ex. Name Structure data 4365-Ethoxy-2-(4-(2-((1- (methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1- yl)benzonitrile

LCMS [M + H]: found 536.2 437 2-(4-(2-((1- (Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)-5-(2-(pyrrolidin-1- yl)ethoxy)benzonitrile

LCMS [M + H]: found 605.2

Example 438.4-(1-(2-Chloro-4-(1-ethylpiperidin-4-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 427, using4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 42) instead of5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile(Example 125, step 1), tert-butyl 4-iodopiperidine-1-carboxylate insteadof tert-butyl 3-iodoazetidine-1-carboxylate, and acetaldehyde instead ofacetone as starting material. LCMS calculated for C₂₇H₃₄ClF₃N₇O₂S(M+H)⁺: m/z=612.2; Found 612.2.

TABLE 44 The compounds in Table 44 were prepared in accordance with thesynthetic protocols set forth in Example 438 using the appropriatestarting materials. Analytical Ex. Name Structure data 4394-(1-(2-Chloro-4-(1- methylpiperidin-4- yl)phenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS [M + H]: found 598.2 440 4-(1-(2-Chloro-4-(1- methylazetidin-3-yl)phenyl)-1H-imidazol-4- yl)-N-(1- (methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine

LCMS [M + H]: found 570.2

Example 441.3-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)oxazolidin-2-one

Step 1:4-(1-(4-(Bromomethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a solution of(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)methanol(Example 231, 226 mg, 0.425 mmol) in DCM (2 mL) was added carbontetrabromide (155 mg, 0.468 mmol) and triphenylphosphine (123 mg, 0.468mmol) at 0° C. The reaction was stirred at room temperature for 2 h.After concentration, the residue was purified by column chromatography(DCM/EtOAc 0-100% gradient). LCMS calculated for C₂₁H₂₂BrClF₃N₆O₂S(M+H)⁺: m/z=593.0; Found 593.0.

Step 2:3-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-H-imidazol-1-yl)benzyl)oxazolidin-2-one

To a solution of oxazolidin-2-one (6.60 mg, 0.076 mmol) in THF (0.253mL) was added sodium hydride (2.425 mg, 0.101 mmol). The mixture wasstirred at room temperature for 5 min before4-(1-(4-(bromomethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(15 mg, 0.025 mmol) was added. The mixture was further stirred at thesame temperature for 1 h. After completion, the reaction mixture wasconcentrated. The residue was then diluted with MeOH and purified byprep HPLC (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₂₆ClF₃N₇O₄S (M+H)⁺: m/z=600.1; Found 600.1.

Example 442.4-(1-(2-Bromophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:4-(1-(4-Amino-2-bromophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inIntermediate 41 using4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 2) instead of4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(Intermediate 38) and 1-fluoro-2-bromo-4-nitrobenzene instead of1,2-difluoro-4-nitrobenzene as starting material. LCMS calculated forC₂₀H₂₂BrF₃N₇O₂S (M+H)⁺: m/z=560.1; Found 560.1.

Step 2:4-(1-(2-Bromophenyl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To4-(1-(4-amino-2-bromophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(359 mg, 0.64 mmol) was added HCl (2.OM aq. solution, 4.0 mL) and sodiumnitrite (221 mg, 3.20 mmol) at 0° C. After stirring for 5 min, sodiumhypophosphite monohydrate (200 mg, 1.921 mmol) was added and the mixturewas stirred at room temperature for 30 min. The reaction was quenched bysodium bicarbonate solution and Na₂S₂O₃ solution and extracted with DCMthree times. The combined organic layers were dried over MgSO₄,filtered, and concentrated. A small fraction of residue was then dilutedwith MeOH and purified by prep HPLC (Sunfire C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₀H₂₁BrF₃N₆O₂S (M+H)⁺: m/z=545.1; Found545.1.

TABLE 45 The compounds in Table 45 were prepared in accordance with thesynthetic protocols set forth in Example 175 using the appropriate aminestarting material. Analytical Ex. Name Structure data 4434-(1-(2,6-Difluoro-4((4- methylpiperazin-1- yl)methyl)phenyl)-1H-imidazol-4-yl)-N- ((3R,4S)-3-fluoro-1- (methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 633.2 444 4-(1-(4- ((Ethylamino)methyl)- 2,6-difluorophenyl)-1H-imidazol-4-yl)-N- ((3R,4S)-3-fluoro-1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 578.1 445 4-(1-(4-((4- Ethylpiperazin-1- yl)methyl)-2-fluorophenyl)-2-methyl- 1H-imidazol-4-yl)-N- ((3R,4S)-3-fluoro-1-(methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 643.3 446 1-(3-Fluoro-4-(4-(2- (((3R,4S)-3-fluoro-1-(methylsulfonyl) piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-2- methyl-1H-imidazol-1- yl)benzyl)-4-methylpiperidin-4-ol

LCMS found 644.2 447 4-(1-(4-((4- Ethylpiperazin-1- yl)methyl)-2,6-difluorophenyl)-1H- imidazol-4-yl)-N- ((3R,45)-3-fluoro-1-(methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 647.3 448 4-(1-(4-(((2,2- Difluoroethyl)amino) methyl)-2-(trifluoromethyl)phenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 628.1 449 3-Methyl-1-(4-(4-(2-((1- (methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-imidazol-1-yl)- 3-(trifluoromethyl)benzyl) azetidin-3-ol

LCMS found 634.2 450 4-(1-(4-(((2,2- Difluoroethyl)amino) methyl)-2-methylphenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 574.3

TABLE 46 The compounds in Table 46 were prepared in accordance with thesynthetic protocols set forth in Example 441 using the appropriatestarting materials. Analytical Ex. Name Structure data 4511-(3-Chloro-4-(4-(2-((1- (methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)benzyl)-4-methylpiperazin- 2-one

LCMS [M + H]: found 627.2 452 1-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)benzyl)azetidin-2-one

LCMS [M + H]: found 584.2 453 1-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3- methylimidazolidin-2-one

LCMS [M + H]: found 613.2 454 1-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl) pyrrolidin-2-one

LCMS [M + H]: found 598.2

TABLE 47 The compounds in Table 47 were prepared in accordance with thesynthetic protocols set forth in Example 101 using the appropriatestarting materials. Analytical Ex. Name Structure data 4551-(1-(3-Fluoro-4-(2-methyl-4- (2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1-yl)phenyl)piperidin-4- yl)pyrrolidin-3-ol

LCMS [M + H]: found 667.3 456 1-(3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1-yl)phenyl)-3-methylazetidin-3-ol

LCMS [M + H]: found 584.2

TABLE 48 The compounds in Table 48 were prepared in accordance with thesynthetic protocols set forth in Example 433 using the appropriatestarting materials. Analytical Ex. Name Structure data 4575-(2-(4-Methylpiperazin-1- yl)ethyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)benzonitrile

LCMS [M + H]: found 618.3 458 2-(4-(2-((1- (Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1-yl)-5-(2-(piperidin-1- yl)ethyl)benzonitrile

LCMS [M + H]: found 603.2

Example 459.4-(1-(4-(3-(Azetidin-1-yl)propyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:3-(3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)propanal

To a mixture of4-(1-(2-fluoro-4-iodophenyl)-2-methy-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(106 mg, 0.170 mmol) and prop-2-en-1-ol (14.8 mg, 0.255 mmol) in DMF(0.42 ml) was added benzyltriethylammonium chloride (38.7 mg, 0.170mmol), sodium bicarbonate (35.7 mg, 0.424 mmol) and palladium(II)acetate (1.9 mg, 8.5 μmol). The mixture was degassed with N₂ and thenstirred in a sealed vial at 55° C. overnight. After cooling to roomtemperature, the reaction mixture was concentrated. The product waspurified by column chromatography (eluting with DCM/EtOAc, 0-100%followed by DCM/MeOH, 0-10%). LCMS calculated for C₂₄H₂₇F₄N₆O₃S (M+H)⁺:m/z=555.2; Found 555.2.

Step 2:4-(1-(4-(3-(Azetidin-1-yl)propyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 157, Step 3, using3-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)propanalinstead of2-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)acetaldehyde(Example 157, step 2) and azetidine instead of dimethylamine as startingmaterial. LCMS calculated for C₂₇H₃₄F₄N₇O₂S (M+H)⁺: m/z=596.2; Found596.2.

TABLE 49 The compound in Table 49 was prepared in accordance with thesynthetic protocols set forth in Example 423 using the appropriatestarting materials. Analytical Ex. Name Structure data 460 4-(1-(4-(3-(Ethyl(methyl)amino) propyl)-2-fluorophenyl)- 2-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS [M + H]: found 598.3

Example 461.4-(2-Bromo-1-(2-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

Step 1:4-(1-(2-Fluorophenyl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

This compound was prepared according to the procedures described inExample 442 using 1,2-difluoro-4-nitrobenzene instead of1-fluoro-2-bromo-4-nitrobenzene as starting material. LCMS calculatedfor C₂₀H₂₁F₄N₆O₂S (M+H)⁺: m/z=485.1; Found 485.1.

Step 2:4-(2-Bromo-1-(2-fluorophenyl)-H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine

To a solution of diisopropylamine (0.17 mL, 1.2 mmol) in 3 mL THE at−78° C. was added n-BuLi in hexanes (0.69 mL, 1.6 M, 1.1 mmol) and themixture stirred 1 min at −78° C. To the LDA solution was added4-(1-(2-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine(219 mg, 0.452 mmol) in THE (3 mL) at −78° C. and the mixture wasstirred at −78° C. for more than 30 min. To the mixture was then addedcarbon tetrabromide (600 mg, 1.808 mmol) in THE (4 mL) and the mixturewas slowly warmed up to room temperature. Then the reaction mixture wasconcentrated. A small fraction of residue was then diluted with MeOH andpurified by prep HPLC (Sunfire C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₀H₂₀BrF₄N₆O₂S (M+H)⁺: m/z=563.0; Found 563.0.

TABLE 50 The compounds in Table 50 were prepared in accordance with thesynthetic protocols set forth in Example 77 using the appropriate aminestarting material. Analytical Ex. Name Structure data 4624-(1-(2-Chloro-3- (((methyl- d3)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 547.2 463 1-(2-Chloro-3-(4-(2-((1- (methylsulfonyl)piperidin- 4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl) azetidine-3-carbonitrile

LCMS found 595.2

TABLE 51 The compounds in Table 51 were prepared in accordance with thesynthetic protocols set forth in Example 369 using the appropriate aminestarting material. Analytical Ex. Name Structure data 4644-(1-(2-Chloro-3-(2-(4- methylpiperazin-1- yl)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 627.2 465 4-(1-(2-Chloro-3-(2- (isopropylamino)ethyl)phenyl)-1H-imidazol- 4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 586.2 466 4-(1-(2-Chloro-3-(2- (ethylamino)ethyl)phenyl)-1H-imidazol- 4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 572.2 467 4-(1-(2-Chloro-3-(2- (methylamino)ethyl)phenyl)-1H-imidazol- 4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine

LCMS found 558.2

TABLE 52 The compounds in Table 52 were prepared in accordance with thesynthetic protocols set forth in Example 375 using the appropriate aminestarting material. Analytical Ex. Name Structure data 4684-(1-(2-Chloro-3-(1- (isopropylamino)ethyl) phenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine

LCMS found 586.2 469 4-(1-(3-(1-(Azetidin-1- yl)ethyl)-2-chlorophenyl)-1H- imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine

LCMS found 584.2

TABLE 53 The compounds in Table 53 were prepared in accordance with thesynthetic protocols set forth in Example 378 using the appropriate aminestarting material. Analytical Ex. Name Structure data 4701-(3-(4-(2-((1- (Methylsulfonyl) piperidin-4-yl) amino)-5-(trifluoromethyl) pyrimidin-4-yl)- 1H-imidazol- 1-yl)-2-(trifluoromethyl) benzyl)azetidine- 3-carbonitrile

LCMS found 629.2 417 (S)-1-(3-(4-(2-((1- (Methylsulfonyl)piperidin-4-yl) amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-imidazol-1-yl)-2- (trifluoromethyl) benzyl)pyrrolidine-3- carbonitrile

LCMS found 643.2

TABLE 54 The compounds in Table 54 were prepared in accordance with thesynthetic protocols set forth in Example 1 using the appropriatestarting materials. Analytical Ex. Name Structure data 4722-(4-(2-(((3R,4S)-3- Fluoro-1-(methylsulfonyl) piperidin-4-yl)amino)-5-(trifluoromethyl) pyrimidin-4-yl)-1H-imidazol- 1-yl)benzonitrile

LCMS found 510.1

Example A. CDK2/Cyclin E1 HTRF Enzyme Activity Assay

CDK2/Cyclin E1 enzyme activity assays utilize full-length human CDK2co-expressed as N-terminal GST-tagged protein with FLAG-Cyclin E1 in abaculovirus expression system (Carna Product Number 04-165). Assays wereconducted in white 384-well polystyrene plates in a final reactionvolume of 8 μL. CDK2/Cyclin E1 (0.25 nM) was incubated with thecompounds of the Examples (40 nL serially diluted in DMSO) in thepresence of ATP (50 μM or 1 mM) and 50 nM ULight™-labeled eIF4E-bindingprotein 1 (THR37/46) peptide (PerkinElmer) in assay buffer (containing50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl₂, 2 mM DTT, 0.05 mg/mL BSA,and 0.01% Tween 20) for 60 minutes at room temperature. The reactionswere stopped by the addition of EDTA and Europium-labeledanti-phospho-4E-BP1 antibody (PerkinElmer), for a final concentration of15 mM and 1.5 nM, respectively. HTRF signals were read after 1 hour atroom temperature on a PHERAstar FS plate reader (BMG Labtech). Data wasanalyzed with IDBS XLFit and GraphPad Prism 5.0 software using a threeor four parameter dose response curve to determine IC₅₀ for eachcompound. The IC₅₀ data as measured for the compounds of the Examples at1 mM ATP in the assay of Example A is shown in Table 55.

TABLE 55 Example IC₅₀ (nM) 1 + 2 + 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 +12 + 13 + 14 + 15 ++ 16 + 17 + 18 + 19 ++ 20 + 21 + 22 + 23 + 24 + 25 +26 + 27 + 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 + 37 + 38 + 39 +40 + 41 + 42 + 43 + 44 + 45 + 46 + 47 + 48 + 49 + 50 + 51 + 52 + 53 +54 + 55 + 56 + 57 + 58 + 59 + 60 + 61 + 62 + 63 + 64 + 65 + 66 + 67 +68 + 69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 + 77 + 78 + 79 + 80 + 81 +82 + 83 + 84 + 85 + 86 + 87 + 88 + 89 + 90 + 91 + 92 + 93 + 94 + 95 +96 + 97 + 98 + 99 + 100 + 101 + 102 + 103 + 104 + 105 + 106 + 107 +108 + 109 + 110 + 111 + 112 + 113 + 114 + 115 + 116 + 117 + 118 + 119 +120 + 121 + 122 + 123 + 124 + 125 + 126 + 127 + 128 + 129 + 130 + 131 +132 + 133 + 134 + 135 + 136 + 137 + 138 + 139 + 140 + 141 + 142 + 143 +144 + 145 + 146 + 147 + 148 + 149 + 150 + 151 + 152 + 153 + 154 + 155 +156 + 157 + 158 + 159 + 160 + 161 + 162 + 163 + 164 + 165 + 166 + 167 +168 + 169 + 170 + 171 + 172 + 173 + 174 + 175 + 176 + 177 + 178 + 179 +180 + 181 + 182 + 183 + 184 + 185 + 186 + 187 + 188 + 189 + 190 + 191 +192 + 193 + 194 + 195 + 196 + 197 + 198 + 199 + 200 + 201 + 202 + 203 +204 + 205 + 206 + 207 + 208 + 209 + 210 + 211 + 212 + 213 + 214 + 215 +216 + 217 + 218 + 219 + 220 + 221 + 222 + 223 + 224 + 225 + 226 + 227 +228 + 229 + 230 + 231 + 232 + 233 + 234 + 235 + 236 + 237 + 238 + 239 +240 + 241 + 242 + 243 + 244 + 245 + 246 + 247 + 248 + 249 + 250 + 251 +252 + 253 + 254 + 255 + 256 + 257 + 258 + 259 + 260 + 261 + 262 + 263 +264 + 265 + 266 + 267 + 268 + 269 + 270 + 271 + 272 + 273 + 274 + 275 +276 + 277 + 278 + 279 + 280 + 281 + 282 + 283 + 284 + 285 + 286 + 287 +288 + 289 + 290 + 291 + 292 + 293 + 294 + 295 + 296 + 297 + 298 + 299 +300 + 301 + 302 + 303 + 304 + 305 + 306 + 307 + 308 + 309 + 310 + 311 +312 + 313 + 314 + 315 + 316 + 317 + 318 + 319 + 320 + 321 + 322 + 323 +324 + 325 + 326 + 327 + 328 + 329 + 330 + 331 + 332 + 333 + 334 + 335 +336 + 337 + 338 + 339 + 340 + 341 + 342 + 343 + 344 + 345 + 346 + 347 +348 + 349 + 350 + 351 + 352 + 353 + 354 + 355 + 356 + 357 + 358 + 359 +360 + 361 + 362 + 363 + 364 + 365 + 366 + 367 + 368 + 369 + 370 + 371 +372 + 373 + 374 + 375 + 376 + 377 + 378 + 379 + 380 + 381 + 382 + 383 +384 + 385 + 386 + 387 + 388 + 389 + 390 + 391 + 392 + 393 + 394 + 395 +396 + 397 + 398 + 399 + 400 + 401 + 402 + 403 + 404 + 405 + 406 + 407 +408 + 409 + 410 + 411 + 412 + 413 + 414 + 415 + 416 + 417 + 418 + 419 +420 + 421 + 422 + 423 + 424 + 425 + 426 + 427 + 428 + 429 + 430 + 431 +432 + 433 + 434 + 435 + 436 + 437 + 438 + 439 + 440 + 441 + 442 + 443 +444 + 445 + 446 + 447 + 448 + 449 + 450 + 451 + 452 + 453 + 454 + 455 +456 + 457 + 458 + 459 + 460 + 461 + 462 + 463 + 464 + 465 + 466 + 467 +468 + 469 + 470 + 471 + 472 + + refers to ≤50 nM ++ refers to >50 nM to200 nM +++ refers to >200 nM to 500 nM ++++ refers to >500 nM to 1000 nM

Example B1. Characterization of Cyclin E1 in Ovarian and EndometrialCancer Cell Lines

The cyclin E1 (“CCNE1”) gene was evaluated in various ovarian andendometrial cancer cell lines (FIGS. 1A and 1B). CCNE1 was amplified inCOV318, OVCAR3 OVARY, Fu-OV1, and KLE cells, each of which displayed aCCNE1 gain of function by copy number (copy number (“CN”)>2) (FIG. 1A).In contrast, CCNE1 was not amplified in COV504, OV56, or Igrov1 cells,each of which displayed copy neutral (2) or loss of function of the gene(CN≤2). CN was obtained from the Broad Institute Cancer Cell LineEncyclopedia (“CCLE”) database (Barretina, et al., Nature, 2012,483(7391):603-7, which is incorporated herein by reference in itsentirety).

Western blot analysis was performed on protein samples from COV318,OVCAR3_OVARY, Fu-OV1, KLE, COV504, OV56, and Igrov1 cells to evaluateCCNE1 protein levels. CCNE1 protein levels were higher in cell lineswith CCNE1 gain of function by copy number (CN>2; i.e., COV318, OVCAR3OVARY, Fu-OV1, and KLE cells) compared to cell lines with copy neutralor loss of function of the gene (CN≤2; i.e., COV504, OV56, and Igrov1cells).

Example B2. CDK2-Knockdown by siRNA Inhibits Proliferation inCCNE1-Amplified, but not CCNE1-Non-Amplified Human Cancer Cell Lines

The effect of CDK2-knockdown in CCNE1-amplified versusCCNE1-non-amplified cell lines was evaluated. CCNE1-amplified cell lines(Fu-OV1 and KLE) or CCNE1-non-amplified cell lines (COV504 and Igrov1)were treated with a control (“ctrl”) or CDK2-specific small interferingRNAs (“siRNAs”) (“CDK2 siRNA-1” and “CDK2 siRNA-2”) (FIGS. 2A and 2B and3A and 3B). Seventy-two hours after transfection with the siRNAs, thecells were harvested and subjected to cell cycle analysis byfluorescence activated cell sorting (“FACS”) (FIGS. 2A and 3A).Knockdown of CDK2 was confirmed by western blot (FIGS. 2B and 3B).CDK2-knockdown inhibited proliferation in CCNE1-amplified cell lines,but not in CCNE1-non-amplified cell lines (FIGS. 2A and 3A).

A similar experiment was performed in additional CCNE1-amplified celllines (COV318, OVCAR3, Fu-OV1, and KLE) and CCNE1-non-amplified celllines (COV504, OV56, and Igrov1) (FIG. 4). The percentage of cells atthe S phase three days after treatment with CDK2-specific siRNAs wassignificantly decreased in CCNE1-amplified cell lines as compared totreatment with control siRNA (FIG. 4). Consistent with the results ofFIGS. 2A and 3A, the percentage of cells at the S phase three days aftertreatment with CDK2-specific siRNAs was not significantly different inCCNE1-non-amplified cell lines as compared to treatment with controlsiRNA (FIG. 4).

Example B3. Proliferation in CCNE1 Amplified and CCNE-Non-Amplified CellLines Upon CDK4/6 Inhibition

The effect of CDK4/6-inhibition in CCNE1-amplified versusCCNE1-non-amplified cell lines was evaluated. CCNE1-amplified cells(OVCAR3) or CCNE1-non-amplified cells (COV504) were treated withdimethyl sulfoxide (“DMSO”) control or increasing concentrations ofCDK4/6 inhibitor palbociclib (FIG. 5). Sixteen hours after treatmentwith DMSO or palbociclib, the cells were harvested and subjected to cellcycle analysis by FACS (FIG. 5). CDK4/6-inhibition resulted indose-dependent inhibition of the proliferation in CCNE1-non-amplifiedcells, but not in CCNE1-amplified cells (FIG. 5).

A similar experiment was performed in a larger set of CCNE1-amplifiedcell lines (COV318 and OVCAR3) and CCNE1-non-amplified cell lines(COV504, OV56, and Igrov1) (FIG. 6). The percentage of cells at the Sphase 16 hours after treatment with palbociclib was decreased inCCNE1-non-amplified cell lines in a dose-dependent fashion as comparedto treatment with DMSO (FIG. 6). Consistent with the results of FIG. 5,the percentage of cells at the S phase 16 hours after treatment withpalbociclib was not significantly different in CCNE1-amplified celllines as compared to treatment with DMSO (FIG. 6).

Example B4. CDK2-Knockdown Blocks Rb Phosphorylation at S780 inCCNE1-Amplified, but not in CCNE1-Non-Amplified, Cell Lines

The effect of CDK2-knockdown on Rb phosphorylation at Ser-780 of SEQ IDNO:3 (“S780”) in CCNE1-amplified versus CCNE1-non-amplified cell lineswas evaluated. CCNE1-amplified cell lines (COV318, Fu-OV1 and KLE) orCCNE1-non-amplified cell lines (COV504, OV56 and Igrov1) were treatedwith ctrl or CDK2-specific siRNAs (FIGS. 7A and 7B). 72 hours aftertransfection with the siRNAs, the cells were harvested and total proteinwas extracted and analyzed by western blot. Knockdown of CDK2 wasconfirmed by western blot. CDK2-knockdown blocked Rb phosphorylation atS780 in CCNE1-amplified cell lines (FIG. 7A), but not inCCNE-non-amplified cell lines (FIG. 7B).

Example B5. Palbociclib Blocks Rb Phosphorylation at S780 in CCNE1Non-Amplified, but not in CCNE1-Amplified, Cell Lines

The effect of CDK4/6-inhibition on Rb phosphorylation at 5780 inCCNE1-amplified versus CCNE1-non-amplified cell lines was evaluated.CCNE1-amplified cell lines (OVCAR3 and COV318) or CCNE1-non-amplifiedcell lines (COV504 and OV56) were treated with DMSO or various doses ofpalbociclib (FIGS. 8A and 8B). One or 15 hours after treatment, thecells were harvested and total protein was extracted and analyzed bywestern blot (FIG. 8). Palbociclib treatment blocked Rb phosphorylationat 5780 in CCNE1-non-amplified cell lines (FIG. 8B), but not inCCNE1-amplified cell lines (FIG. 8A).

Example B6. CDK2 Degradation by dTAG Decreases Rb Phosphorylation atS780

To further confirm that CDK2 knockdown decreases Rb phosphorylation atS780 in CCNE1-amplified cells (see Example B4), the dTAG system was usedto degrade CDK2 and the level of 5780-phosphorylated Rb was evaluated(Erb et al., Nature, 2017, 543(7644):270-274, which is incorporatedherein by reference in its entirety). Briefly, OVCAR3 cells wereengineered to express Cas9 by lentiviral transduction of Cas9 construct.The OVCAR3-Cas9 cells were then engineered to express CDK2-FKBP12F36V-HAfusion protein by lentiviral transduction of CDK2-FKBP12F36V-HAexpression construct. Next, to engineer the line to have endogenous CDK2inactivated, OVCAR3 (Cas9, CDK2-FKBP12F36V-HA) cells were transducedwith CDK2 sgRNA (“CDK2-gRNA”); OVCAR3 (Cas9, CDK2-FKBP12F36V-HA) cellstransduced with non-targeting sgRNA (“Ctl-gRNA”; Cellecta) served as acontrol cell line.

To degrade CDK2-FKBP12F36V-HA protein by dTAG (FIG. 9A), cells weretreated with DMSO or with a titration of concentrations of dTAG for 14hours. Cells were collected and processed for Western blot (FIG. 9B). Adose-responsive degradation of CDK2-FKBP12(F36V) was detected by westernblot after treatment with dTAG in both control- and CDK2-gRNA treatedcells (FIG. 9B). Degradation was further confirmed by western blot forHA-Tag. Endogenous CDK2 protein was detected in OVCAR3 cells treatedwith control gRNA, but not with CDK2-gRNA (FIG. 9B). CDK2-FKBP12(F36V)degradation inhibited Rb phosphorylation at S780 in CDK2 knockout OVCAR3cells, but not in OVCAR3 cells with endogenous CDK2 expression.

Example B7. p-Rb S780 HTRF Cellular Assay for Identification of CDK2Inhibitors

An in vitro CDK2/CCNE1 enzyme activity assay was used to measurephosphorylation of a peptide substrate using homogenous time-resolvedenergy transfer (“HTRF”). First, the specificity of8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound A; see US Patent Application Publication No. 2018/0044344 atpage 51, paragraph [0987], which is incorporated by reference herein inits entirety) for CDK2 inhibition was confirmed via a kinase activityassay (FIG. 10A). To this end, the LANCE® Ultra kinase assay was usedwith a ULight™-labeled EIF4E-binding protein 1 (Thr37/46) peptide(PerkinElmer, TRF0128-M) as substrate and an Europium-labeledanti-phospho-EIF4E binding protein1 (Thr37/46) antibody (PerkinElmer,TRF0216-M). A ratio of fluorescence transferred to the labeled substrate(665 nm) relative to fluorescence of the Europium donor (620 nm)represents the extent of phosphorylation. The IC₅₀ for Compound A wasdetermined to be 1.1 nM (FIG. 10A). In contrast, the IC₅₀ for the CDK4/6inhibitor palbociclib was 10,000 nM (FIG. 10A).

Next, a CDK2 pRb (S780) HTRF cellular assay was performed, enabling thequantitative detection of Rb phosphorylated on serine 780 in CCNE1amplified COV318 cells upon treatment with Compound A or palbociclib(FIG. 10B). Treatment with Compound A, but not palbociclib, inhibited Rbphosphorylation on serine 780 in CCNE1 amplified cells (FIG. 10B). TheIC₅₀ for Compound A in this assay was 37 nM, while the IC₅₀ forpalbociclib was >3,000 nM (FIG. 10B).

Example B8. Bioinformatics Analysis of CCLE Dataset Reveals theSensitivity to CDK2 Inhibition in CCNE1 Amplified Cells Relies onFunctional p16

In an attempt to identify a biomarker for predicting sensitivity toCDK2-inhibition in CCNE1-amplified cells, 460 cell lines from CCLE wereanalyzed (Barretina, supra). First, the cell lines were filtered basedon CCNE1 copy number and expression and CDK2 sensitive score based onshRNA knockdown data. A total of 41 cell lines were identified as havingCCNE1 copy number of >3 and CCNE1 expression score (CCLE: >3). Of these41 cell lines, 18 (44%) were sensitive to CDK2 inhibition (CDK2sensitive score≤−3), while 23 (56%) were insensitive to CDK2 inhibition(CDK2 sensitive score>−3).

Next, the p16 status was evaluated in the CDK2-sensitive andCDK2-insensitive cell lines (FIG. 11). Of the 18 cell lines that weresensitive to CDK2-inhibition, 100% expressed normal p16 gene (FIG. 11).In contrast, only 4 of the 23 CDK2-insensitive cell lines expressednormal p16 gene (FIG. 11). The majority of the 23 CDK2-insensitive celllines displayed dysfunctional p16 gene expression: the p16 gene wasdeleted in 10 of 23 cell lines; the p16 gene was silenced in 5 of the 23cell lines, and the p16 gene was mutated in 4 of the 23 cell lines (FIG.11).

A summary of CDK2 sensitivity and CDKN2A/p16 status in CCNE1 amplifiedcell lines is provided in Table 56, below.

TABLE 56 Cell lines with CDK2 sensitive Score ≤3 counted as CDK2Sensitive lines; ≥3 as CDK2 insensitive line. Cell lines verified inexperiments are in bold. NCIN87_STOMACH showed no CDKN2A/P16 proteinexpression in western blot. CCNE1 and CDKN2A/P16 copy number werecalculated based on CCLE dataset. Expression Score <0 counted as genesilencing. CDKN2A/p CDK2 CCNE1 CDKN2 16 mRNA CDKN2a/ sensitive Copy ACopy Expression p16 Cell Lines Score No. No. Score DysfunctionHCC1569_BREAST −9.6 16 2 5.11 OVISE_OVARY −9.4 3 2 4.17 MKN1_STOMACH−8.9 5 1 4.28 EFE184_ENDOMETRIUM −8.7 3 2 3.97 KURAMOCHI_OVARY −8.2 3 23.60 MKN7_STOMACH −7.7 21 1 4.37 MDAMB157_BREAST −7.6 6 2 5.01HCC70_BREAST −7.6 4 4 4.88 NIHOVCAR3_OVARY −7.4 10 2 4.15 FUOV1_OVARY −710 3 5.19 KLE_ENDOMETRIUM −7 7 2 6.24 COV318_OVARY −7 14 2 5.09CAOV4_OVARY −6.7 3 2 3.59 MFE280_ENDOMETRIUM −6.3 4 2 4.97 NCIH661_LUNG−6.2 5 2 3.73 OVCAR4_OVARY −4.3 4 1 4.77 SNU8_OVARY −3.8 5 3 5.35OVCAR8_OVARY −3.7 3 2 5.21 RMUGS_OVARY −2.8 4 1 −0.08 SilencingNCCSTCK140_STOMACH −2.7 3 0 −4.70 Deletion NCIH2286_LUNG −1.6 3 1 3.63Mutation HOP62_LUNG −1.4 4 0 −1.21 Deletion LN340_CENTRAL_NERVOUS_SYSTEM−1.0 3 0 −5.47 Deletion NCIH1339_LUNG −0.8 3 2 2.42 UnknownNCIN87_STOMACH 0.1 3 2 4.67 No preteen U2OS_BONE 0.4 3 1 −5.72 SilencingSF172_CENTRAL_NERVOUS_SYSTEM 0.5 3 0 −2.35 Deletion CAL120_BREAST 0.6 41 4.86 RMGI_OVARY 0.9 3 0 −3.33 Deletion OV90_OVARY 0.9 3 1 3.95Mutation SNU601_STOMACH 1.1 4 2 −3.79 Silencing EW8_BONE 1.5 5 1 3.11JHESOAD1_OESOPHAGUS 1.7 5 0 −5.52 Deletion HCC1806_BREAST 1.9 8 0 −4.61Deletion NCIH2170_LUNG 2.0 3 0 −3.73 Deletion HCC1428_BREAST 2.3 3 22.28 A549_LUNG 2.5 4 0 −6.13 Deletion LXF289_LUNG 2.6 4 3 4.10 MutationAGS_STOMACH 3.0 3 2 −5.56 Silencing NCIH647_LUNG 3.0 4 0 −5.07 DeletionHLF_LIVER 3.9 3 2 3.40

Example B9. CCNE1 Amplified Cells with Dysfunctional p16 do not Respondto CDK2 Inhibition

To further evaluate the role of p16 in CDK2-sensitivity inCCNE-amplified cells, p16 protein expression in three gastric cell lineswith CCNE1-amplification was evaluated by western blot. AGS and NCI-N87cells displayed absent or dramatically reduced levels of p16 (FIG. 12A).In contrast, p16 protein was detected in MKN1 cellular protein extracts(FIG. 12A).

Next, the impact of CDK2-knockdown in these cells was evaluated. Mkn1,Ags, and NCI-N87 cells were treated with control or CDK2-specific siRNA.Three days-post-siRNA transfection, cell cycle phase distribution of thecells was evaluated by FACS. The percentage of cells at the S phase inthe Mkn1 cells (CCNE-amplified, p16 protein detected) was significantlydecreased in the CDK2 siRNA-treated cells as compared to control (FIG.12B). In contrast, the percentage of cells at the S phase was notsignificantly decreased in Ags and NCI-N87 cells (CCNE1-amplified,dysfunctional p16 protein levels) after treatment with CDK2 siRNA ascompared to control (FIG. 12B).

Example B10. p16 Knockdown by siRNA Abolishes CDK2 Inhibition InducedCell Cycle Suppression in CCNE1 Amplified Cells

To confirm the role of p16 in CDK2-sensitivity of CCNE-amplified cells,COV318 cells were treated with control or p16-specific siRNA.Seventy-two hours after transfection, cells were treated with DMSO(control) or 100 nM of Compound A. Sixteen hours after treatment withDMSO or the CDK2-inhibitor, cells were harvested and subjected to cellcycle analysis by FACS. Consistent with the results described above, thepercentage of S phase cells significantly decreased in the controlsiRNA-treated cells treated with CDK2-inhibitor (Compound A), but notwith the DMSO control (FIG. 13). In contrast, the percentage of S phasecells was not significantly decreased after treatment with theCDK2-inhibitor (Compound A) in p16 knocked down cells as compared toDMSO control (FIG. 13).

Materials and Methods Used in Examples B1-B10

Cell Culture and Transfection

Human cyclin E1 (CCNE1) amplified ovarian cell lines OVCAR3, COV318,Fu-OV1, endometrial cell line KLE, gastric cell lines MKN1, AGS, NCIN87,and CCNE1 non-amplified ovarian cell lines COV504, OV56, Igrov1 werecultured in RPMI 1640 medium. The complete growth medium wassupplemented with 10% FBS, 0.1 mM non-essential amino acids, 2 mML-glutamine, 100 units/mL penicillin G and 100 μg/mL streptomycin in 37°C. humidified incubator and an atmosphere of 5% CO₂ in air. Fu-OV1 linewas purchased from Leibniz-Institute DSMZ—German Collection ofMicroorganisms and Cell Cultures; MKN1 was purchased from JapaneseCancer Research Resources Bank; and the rest of cell lines werepurchased from American Type Culture Collection. For transfection, cellswere seeded into 6-well for 24 hours and transiently transfected byLipofectamine 2000 Reagent (Thermo Fisher, 11668027). ON-TARGETplusHuman CKD2 siRNAs (GE Healthcare Dharmacon, J-003236-11-0002 andJ-003236-12-0002) and ON-TARGETplus Human CDKN2A/p16 siRNAs (GEHealthcare Dharmacon, J-011007-08-0002) were used to knockdown theendogenous CDK2 and CDKN2A/p16. ON-TARGETplus Non-targeting Pool (GEHealthcare Dharmacon, D-001810-10-20) was used as a negative control.

Western Blot Analysis

Whole cell extracts were prepared using RIPA buffer (Thermo Scientific,89900) with a Halt Protease and Phosphatase Inhibitor Cocktail (ThermoScientific, 78440). Protein concentration was quantified with a BCAProtein Assay Kit (Thermo Scientific, 23225) and 40 μg of proteinlysates were loaded for SDS-PAGE using precast gradient gels (Bio-Rad,Hercules, No. 456-1094). Samples were diluted in 5× Laemmli buffer (300mM Tris-HCl pH 6.8, 10% SDS (w/v), 5% 2-mercaptoethanol, 25% glycerol(v/v), 0.1% bromophenol blue w/v) and boiled for 5 minutes. 35 g ofproteins were separated by 8-15% SDS-PAGE and transferred ontopolyvinylidene fluoride (PVDF) membranes. Unspecific binding sites onthe PVDF membranes were blocked with 5% non-fat milk in TBST (20 mMTris-HCl, pH 7.6, 137 mM NaCl, 1% Tween-20). Membranes were hybridizedwith antibodies against anti-CDKN2A/p16 (Cell Signaling Technology,92803S), anti-Cas9 (Cell Signaling Technology, 97982S), anti-HA (CellSignaling Technology, 3724S), anti-Rb (Cell Signaling Technology,9309S), anti-phospho-Rb (Ser780) (Cell Signaling Technology, 8180S),anti-CDK2 (Cell Signaling Technology, 2546S), anti-CCNE1 (Cell SignalingTechnology, 20808S) and anti-GAPDH (Cell Signaling Technology, 8884S)for overnight at 4° C., followed by incubation with horseradishperoxidase(HRP)-conjugated secondary antibodies for 1 hour at roomtemperature. The membranes were then developed using Immobilon Westernchemiluminescence HRP substrates (Millipore, WBKLS0500). Images werecaptured by Luminescence/Fluorescence Imaging System Odyssey CLx Imager(LI-COR).

Cell Cycle Analysis

Cells were seeded in six-well tissue culture plates and 24 hours laterwere treated with a titration of concentrations of Palbociclib orCompound A. After overnight treatment, cells exposed to 10 μM EdU for 3hours before detection of EdU-DNA by Click-iT AlexaFluor® 647 azide kit(Life Technology, C10424) following the manufacturer's instructions.Bulk DNA was stained with DAPI. Compound-treated and DMSO treatedcontrol cells were acquired with CytoFlex (Beckman Coulter) and wereanalyzed using the FlowJo software. For cell cycle analysis of cellswith siRNA knockdown, 72 hours after siRNA transfection, cells exposedto 10 M EdU for 3 hours before detection of Click-iT Alexa Fluor® 647azide kit.

Plasmids

LentiCas9 plasmid pRCCH-CMV-Cas9-2A (Cellecta, SVC9-PS) was used forCas9 expression. sgRNA-CDK2 lentiviral construct, designed to targetAAGCAGAGATCTCTCGGA (SEQ ID NO:8) of CDK2, was cloned into sgRNAexpression vector pRSG-U6 and purchased from Cellecta (93661). ForCDK2-FKBP12F36V-HA expression, a 1306 base pair DNA fragment encodingCDK2 and FKBP12F36V-2xHA tag at the C-terminus was synthesized andcloned into EcoRI and BamHI digested pCDH-EF1α-MCS-T2A-Puro lentivector(Systembio, CD527A-1).

Sequence of 1306 bp DNA Fragment:

(SEQ ID NO: 4) CCTCGAATTCAGC TGCATGGAGAACTTCCAAAAGGTGGAAAAGATCGGAGAGGGCACGTACGGAGTTGTGTACAAAGCCAGAAACAAGTTGACGGGAGAGGTGGTGGCGCTTAAGAAAATCCGCCTGGACACTGAGACTGAGGGTGTGCCCAGTACTGCCATCCGAGAGATCTCTCTGCTTAAGGAGCTTAACCATCCTAATATTGTCAAGCTGCTGGATGTCATTCACACAGAAAATAAACTCTACCTGGTTTTTGAATTTCTGCACCAAGATCTCAAGAAATTCATGGATGCCTCTGCTCTCACTGGCATTCCTCTTCCCCTCATCAAGAGCTATCTGTTCCAGCTGCTCCAGGGCCTAGCTTTCTGCCATTCTCATCGGGTCCTCCACCGAGACCTTAAACCTCAGAATCTGCTTATTAACACAGAGGGGGCCATCAAGCTAGCAGACTTTGGACTA GCCAGAGCTTTTGGAGT ACCTGTTCGTACTTACACCCATGA A GTGGTGACCCTGTGGTACCGAGCTCCTGAAATCCTCCTGGGCTGCAAATATTATTCCACAGCTGTGGACATCTGGAGCCTGGGCTGCATCTTTGCTGAGATGGTGACTCGCCGGGCCCTATTCCCTGGAGATTCTGAGATTG ACCAGCTCTT TCGGATCTTTCGGACTCTGGGGACCCCAGATGAGGTGGTGTGGCCAGGAGTTACTTCTATGCCTGATTACAAGCCAAGTTTCCCCAAGTGGGCCCGGCAAGATTTTAGTAAAGTTGTACCTCCCCTGGATGAAGATGGACGGAGCTTGTTATCGCAAATGCTGCACTACGACCCTAACAAGCGGATTTCGGCCAAGGCAGCCCTGGCTCACCCTTTCTTCCAGGATGTGACCAAGCCAGTACCCCATCTTCGA CTCGGAGTGCAGGTGGAAACCATCTCCCCAGGAGACGGGCGCACCTTCCCCAAGCGCGGCCAGACCTGCGTGGTGCACTACACCGGGATGCTTGAAGATGGAAAGAAAGTTGATTCCTCCCGGGACAGAAACAAGCCCTTTAAGTTTATGCTAGGCAAGCAGGAGGTGATCCGAGGCTGGGAAGAAGGGGTTGCCCAGATGAGTGTGGGTCAGAGAGCCAAACTGACTATATCTCCAGATTATGCCTATGGTGCCACTGGGCACCCAGGCATCATCCCACCACATGCCACTCTCGTCTTCGATGTGGAGCTTCTAAAACTGGAAGGATACCCTTACGACGTTCCTGATTACGCTTACCCTTACGACGTTCCTGATTACGCT GGATCCTAATTCGAAAGC

GAATTC (SEQ ID NO:5; EcoRI), GGATCC (SEQ ID NO:6; BamHI) and TTCGAA (SEQID NO:7; BstBI) restriction enzyme sites were underlined. Sequenceencoding CDK2 is in bold and sequence of FKBP12F36V-HA is in italics.Three nucleic acids underlined within the CDK2 sequence indicatedmodifications that abolished PAM sites to avoided CRISPR knockouteffect. These changes did not change amino acids encoded.

Lentivirus Production

Production of lentivirus was performed in 293T cells by co-transfectionof Lentiviral Packaging Mix (Sigma, SHP001), and a given lentiviralexpression plasmid using Lipofectamine 2000. Viral supernatants werecollected 48 and 72 hours after transfection, filtered through a 0.22 μmmembrane. All cells lines were transduced by spinoculation at 2000revolutions per minute (rpm) for 1 hour at room temperature with 8 μg/mLpolybrene (Santa Cruz, sc-134220).

CDK2-dTAG Cells

OVCAR3 cells were first engineered to express Cas9 by lentiviraltransduction of Cas9 construct. Cells were selected and maintained in100 μg/mL hygromycin (Life Technologies, 10687010) and verified toexpress Cas9 by immunoblot. OVCAR3-Cas9 cells were then engineered toexpress CDK2-FKBP12F36V-HA fusion protein by lentiviral transduction ofCDK2-FKBP12F36V-HA expression construct and selection with 2 μg/mLpuromycin dihydrochloride (Life Technologies, A1113803). Expression ofCDK2-FKBP12F36V-HA was verified by immunoblot using anti-CDK2 andanti-HA antibodies. Next, to engineer the line to have endogenous CDK2inactivated, OVCAR3 (Cas9, CDK2-FKBP12F36V-HA) cells were transducedwith CDK2 sgRNA and selected by 50 μg/mL Zeocin (Life Technologies,R25001). Inactivated expression of endogenous CDK2 in the expandedclones was tested by immunoblotting. OVCAR3 (Cas9, CDK2-FKBP12F36V-HA)cells transduced with non-targeting sgRNA (Cellecta) were served as acontrol cell line.

To degrade CDK2-FKBP12F36V-HA protein by dTAG, 200,000 cells were seededin 1 mL media in triplicate in a 24-well plate and treated with dimethylsulfoxide (DMSO) or with a titration of concentrations of dTAG for 14hours. Cells were collected and processed for Western blot.

CDK2 CCNE1 Enzymatic Assay

In vitro CDK2/CCNE1 enzyme activity assay measures phosphorylation of apeptide substrate using homogeneous time-resolved energy transfer(HTRF). The LANCE® Ultra kinase assay used a ULight™-labeledEIF4E-binding protein 1 (Thr37/46) peptide (PerkinElmer, TRF0128-M) assubstrate and an Europium-labeled anti-phospho-EIF4E binding protein1(Thr37/46) antibody (PerkinElmer, TRF0216-M). A ratio of fluorescencetransferred to the labeled substrate (665 nm) relative to fluorescenceof the Europium donor (620 nm) represents the extent of phosphorylation.Ratios for treated wells are normalized to DMSO only (100% activity) andno enzyme (0% activity) controls. Normalized data is analyzed using afour parameter dose response curve to determine IC₅₀ for each compound.

CDK2 pRb (S780) HTRF Cellular Assay

CDK2 pRb (5780) HTRF cellular assay enables the quantitative detectionof Rb phosphorylated on serine 780 in CCNE1 amplified COV318 cells. Theassay comprised two antibodies: Europium cryptate labeledanti-Phospho-Rb S780 antibody (donor) and d2 labeled anti-Rb antibody(acceptor). In brief, COV318 cells were seeded into the wells of 96-wellplate at a density of 25,000 per well with 9-point, 3-fold serialdiluted compounds and cultured overnight at 37 degree with 5% CO₂. Thefinal concentrations of compounds start from 3 μM. The next day cellswere lysed in 70 μL 1× Phospho-total protein lysis buffer #2 (Cisbio),supplemented with 0.7 μL blocking buffer (Cisbio) and 1.4 μL proteaseinhibitor cocktail set III, EDTA-free (Calbiochem, 539134). 16 μL ofcell lysates were mixed with 4 μL of the fluorophore-conjugatedantibodies to a final concentration of 0.188 nM cryptate-labeledanti-Phospho-Rb S780 antibody and 0.14 nM d2 labeled anti-Rb antibody.After 2h of incubation at room temperature, HTRF signals were measuredon the PHERAstar microplate reader (BMG Labtech), using 340 nm asexcitation wavelength, a 620 nm filter for the Europium donorfluorescence, and a 665-nm filter for the acceptor fluorescencedetection. HTRF signals were calculated as the HTRF ratio (ratio offluorescence measured at 665 nm and 620 nm)×10000.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound which is:

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 3.The compound of claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, which is:


5. A pharmaceutical composition comprising a compound of claim 3, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 6. A pharmaceutical composition comprising acompound of claim 4, and a pharmaceutically acceptable carrier.
 7. Thecompound of claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, which is:


9. A pharmaceutical composition comprising a compound of claim 7, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 10. A pharmaceutical composition comprising acompound of claim 8, and a pharmaceutically acceptable carrier.
 11. Thecompound of claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, which is:


13. A pharmaceutical composition comprising a compound of claim 11, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 14. A pharmaceutical composition comprising acompound of claim 12, and a pharmaceutically acceptable carrier.
 15. Thecompound of claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1, which is:


17. A pharmaceutical composition comprising a compound of claim 15, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 18. A pharmaceutical composition comprising acompound of claim 16, and a pharmaceutically acceptable carrier.
 19. Thecompound of claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 20. The compound of claim1, which is:


21. A pharmaceutical composition comprising a compound of claim 19, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 22. A pharmaceutical composition comprising acompound of claim 20, and a pharmaceutically acceptable carrier.